Prion: Difference between revisions

Prion
Prion
	3D structure of major prion protein
Pronunciation	/ˈpriːɒn/ ⓘ, /ˈpraɪɒn/ ;
Specialty	Infectious diseases

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A prion /ˈpriːɒn/ ^ⓘ is a misfolded protein that can induce misfolding of normal variants of the same protein and trigger cellular death. Prions cause prion diseases known as transmissible spongiform encephalopathies (TSEs) that are fatal transmissible neurodegenerative diseases in humans and animals.^[3]^[4] The proteins may misfold sporadically, due to genetic mutations, or by exposure to an already misfolded protein.^[5] The consequent abnormal three-dimensional structure confers on them the ability to cause misfolding of other proteins.

The word prion is derived from the term "proteinaceous infectious particle".^[6]^[7] The hypothesized role of a protein as an infectious agent stands in contrast to all other known infectious agents such as viroids, viruses, bacteria, fungi, and parasites, all of which contain nucleic acids (DNA, RNA, or both).

Most prions are twisted isoforms of the major prion protein (PrP), a natural protein whose normal function is uncertain. They are hypothesized as the cause of transmissible spongiform encephalopathies (TSEs),^[8] including scrapie in sheep, chronic wasting disease (CWD) in deer, bovine spongiform encephalopathy (BSE) in cattle (mad cow disease), feline spongiform encephalopathy (FSE) in felines, and Creutzfeldt–Jakob disease (CJD) and fatal insomnia in humans.

All known prion diseases in mammals affect the structure of the brain or other neural tissue; all are progressive, have no known effective treatment, and are always fatal.^[9] All mammalian prion diseases were believed to be caused by PrP, until 2015, when a prion form of alpha-synuclein was hypothesized to cause multiple system atrophy (MSA).^[10]

Prions are a type of intrinsically disordered protein, which continuously change their conformation unless they are bound to a specific partner such as another protein. With a prion, two protein chains are stabilized if one binds to another in the same conformation. The probability of this happening is low, but once it does, the combination of the two is very stable. Then more units can get added, making a sort of "fibril".^[11] Prions form abnormal aggregates of proteins called amyloids, which accumulate in infected tissue and are associated with tissue damage and cell death.^[12] Amyloids are also associated with several other neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease.^[13]^[14]

A prion disease is a type of proteopathy, or disease of structurally abnormal proteins. In humans, prions are believed to be the cause of Creutzfeldt–Jakob disease (CJD), its variant (vCJD), Gerstmann–Sträussler–Scheinker syndrome (GSS), fatal familial insomnia (FFI), and kuru.^[15] There is also evidence suggesting prions may play a part in the process of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS); these have been termed prion-like diseases.^[16]^[17]^[18]^[19] Several yeast proteins have also been identified as having prionogenic properties,^[20]^[21] as well as a protein involved in modification of synapses during the formation of memories^[22]^[11] (see Eric Kandel § Molecular changes during learning). Prion replication is subject to epimutation and natural selection just as for other forms of replication, and their structure varies slightly between species.^[23]

Prion aggregates are stable, and this structural stability means that prions are resistant to denaturation by chemical and physical agents: they cannot be destroyed by ordinary disinfection or cooking. This makes disposal and containment of these particles difficult, and the risk of iatrogenic spread through medical instruments a growing concern.

Etymology and pronunciation

The word prion, coined in 1982 by Stanley B. Prusiner, is derived from protein and infection, hence prion,^[24] and is short for "proteinaceous infectious particle",^[10] in reference to its ability to self-propagate and transmit its conformation to other proteins.^[25] Its main pronunciation is /ˈpriːɒn/ ^ⓘ,^[26]^[27]^[28] although /ˈpraɪɒn/, as the homographic name of the bird (prions or whalebirds) is pronounced,^[28] is also heard.^[29] In his 1982 paper introducing the term, Prusiner specified that it is "pronounced pree-on".^[24]

Prion protein

Structure

Prions consist of a misfolded form of major prion protein (PrP), a protein that is a natural part of the bodies of humans and other animals. The PrP found in infectious prions has a different structure and is resistant to proteases, the enzymes in the body that can normally break down proteins. The normal form of the protein is called PrP^C, while the infectious form is called PrP^Sc – the C refers to 'cellular' PrP, while the Sc refers to 'scrapie', the prototypic prion disease, occurring in sheep.^[30] PrP can also be induced to fold into other more-or-less well-defined isoforms in vitro; although their relationships to the form(s) that are pathogenic in vivo is often unclear, high-resolution structural analyses have begun to reveal structural features that correlate with prion infectivity.^[31]

PrP^C

PrP^C is a normal protein found on the membranes of cells, "including several blood components of which platelets constitute the largest reservoir in humans."^[32] It has 209 amino acids (in humans), one disulfide bond, a molecular mass of 35–36 kDa and a mainly alpha-helical structure.^[33]^[34] Several topological forms exist; one cell surface form anchored via glycolipid and two transmembrane forms.^[35] The normal protein is not sedimentable; meaning that it cannot be separated by centrifuging techniques.^[36] It has a complex function, which continues to be investigated. PrP^C binds copper(II) ions (those in a +2 oxidation state) with high affinity.^[37] The significance of this property is not clear, but it is presumed^{[by whom?]} to relate to the protein's structure or function. PrP^C is readily digested by proteinase K and can be liberated from the cell surface by the enzyme phosphoinositide phospholipase C (PI-PLC), which cleaves the glycophosphatidylinositol (GPI) glycolipid anchor.^[38] PrP plays an important role in cell-cell adhesion and intracellular signaling in vivo,^[39] and may therefore be involved in cell-cell communication in the brain.^[40]

PrP^Sc

The infectious isoform of PrP, known as PrP^Sc, or simply the prion, is able to convert normal PrP^C proteins into the infectious isoform by changing their conformation, or shape; this, in turn, alters the way the proteins interconnect. PrP^Sc always causes prion disease. PrP^Sc has a higher proportion of β-sheet structure in place of the normal α-helix structure.^[41]^[42]^[43] Several highly infectious, brain-derived PrP^Sc structures have been discovered by cryo-electron microscopy.^[44]^[45]^[46] Another brain-derived fibril structure isolated from humans with Gerstmann-Straussler-Schienker syndrome has also been determined.^[47] All of the structures described in high resolution so far are amyloid fibers in which individual PrP molecules are stacked via intermolecular beta sheets. However, 2-D crystalline arrays have also been reported at lower resolution in ex vivo preparations of prions.^[48] In the prion amyloids, the glycolipid anchors and asparagine-linked glycans, when present, project outward from the lateral surfaces of the fiber cores. Often PrP^Sc is bound to cellular membranes, presumably via its array of glycolipid anchors, however, sometimes the fibers are dissociated from membranes and accumulate outside of cells in the form of plaques. The end of each fiber acts as a template onto which free protein molecules may attach, allowing the fiber to grow. This growth process requires complete refolding of PrP^C.^[49] Different prion strains have distinct templates, or conformations, even when composed of PrP molecules of the same amino acid sequence, as occurs in a particular host genotype.^[50]^[51]^[52]^[53]^[54] Under most circumstances, only PrP molecules with an identical amino acid sequence to the infectious PrP^Sc are incorporated into the growing fiber.^[36] However, cross-species transmission also happens rarely.^[55]

PrP^res

Protease-resistant PrP^Sc-like protein (PrP^res) is the name given to any isoform of PrP^c which is structurally altered and converted into a misfolded proteinase K-resistant form.^[56] To model conversion of PrP^C to PrP^Sc in vitro, Kocisko et al. showed that PrP^Sc could cause PrP^C to convert to PrP^res under cell-free conditions ^[57] and Soto et al. demonstrated sustained amplification of PrP^res and prion infectivity by a procedure involving cyclic amplification of protein misfolding.^[58] The term "PrP^res" may refer either to protease-resistant forms of PrP^Sc, which is isolated from infectious tissue and associated with the transmissible spongiform encephalopathy agent, or to other protease-resistant forms of PrP that, for example, might be generated in vitro.^[59] Accordingly, unlike PrP^Sc, PrP^res may not necessarily be infectious.

Normal function of PrP

The physiological function of the prion protein remains poorly understood. While data from in vitro experiments suggest many dissimilar roles, studies on PrP knockout mice have provided only limited information because these animals exhibit only minor abnormalities. In research done in mice, it was found that the cleavage of PrP in peripheral nerves causes the activation of myelin repair in Schwann cells and that the lack of PrP proteins caused demyelination in those cells.^[60]

PrP and regulated cell death

MAVS, RIP1, and RIP3 are prion-like proteins found in other parts of the body. They also polymerise into filamentous amyloid fibers which initiate regulated cell death in the case of a viral infection to prevent the spread of virions to other, surrounding cells.^[61]

PrP and long-term memory

A review of evidence in 2005 suggested that PrP may have a normal function in maintenance of long-term memory.^[62] As well, a 2004 study found that mice lacking genes for normal cellular PrP protein show altered hippocampal long-term potentiation.^[63]^[64] A recent study that also suggests why this might be the case, found that neuronal protein CPEB has a similar genetic sequence to yeast prion proteins. The prion-like formation of CPEB is essential for maintaining long-term synaptic changes associated with long-term memory formation.^[65]

PrP and stem cell renewal

A 2006 article from the Whitehead Institute for Biomedical Research indicates that PrP expression on stem cells is necessary for an organism's self-renewal of bone marrow. The study showed that all long-term hematopoietic stem cells express PrP on their cell membrane and that hematopoietic tissues with PrP-null stem cells exhibit increased sensitivity to cell depletion.^[66]

PrP and innate immunity

There is some evidence that PrP may play a role in innate immunity, as the expression of PRNP, the PrP gene, is upregulated in many viral infections and PrP has antiviral properties against many viruses, including HIV.^[67]

Replication

The first hypothesis that tried to explain how prions replicate in a protein-only manner was the heterodimer model.^[68] This model assumed that a single PrP^Sc molecule binds to a single PrP^C molecule and catalyzes its conversion into PrP^Sc. The two PrP^Sc molecules then come apart and can go on to convert more PrP^C. However, a model of prion replication must explain both how prions propagate, and why their spontaneous appearance is so rare. Manfred Eigen showed that the heterodimer model requires PrP^Sc to be an extraordinarily effective catalyst, increasing the rate of the conversion reaction by a factor of around 10¹⁵.^[69] This problem does not arise if PrP^Sc exists only in aggregated forms such as amyloid, where cooperativity may act as a barrier to spontaneous conversion. What is more, despite considerable effort, infectious monomeric PrP^Sc has never been isolated.^[70]

An alternative model assumes that PrP^Sc exists only as fibrils, and that fibril ends bind PrP^C and convert it into PrP^Sc. If this were all, then the quantity of prions would increase linearly, forming ever longer fibrils. But exponential growth of both PrP^Sc and of the quantity of infectious particles is observed during prion disease.^[71]^[72]^[73] This can be explained by taking into account fibril breakage.^[74] A mathematical solution for the exponential growth rate resulting from the combination of fibril growth and fibril breakage has been found.^[75] The exponential growth rate depends largely on the square root of the PrP^C concentration.^[75] The incubation period is determined by the exponential growth rate, and in vivo data on prion diseases in transgenic mice match this prediction.^[75] The same square root dependence is also seen in vitro in experiments with a variety of different amyloid proteins.^[76]

The mechanism of prion replication has implications for designing drugs. Since the incubation period of prion diseases is so long, an effective drug does not need to eliminate all prions, but simply needs to slow down the rate of exponential growth. Models predict that the most effective way to achieve this, using a drug with the lowest possible dose, is to find a drug that binds to fibril ends and blocks them from growing any further.^[77]

Researchers at Dartmouth College discovered that endogenous host cofactor molecules such as the phospholipid molecule (e.g. phosphatidylethanolamine) and polyanions (e.g. single stranded RNA molecules) are necessary to form PrP^Sc molecules with high levels of specific infectivity in vitro, whereas protein-only PrP^Sc molecules appear to lack significant levels of biological infectivity.^[78]^[79]

Transmissible spongiform encephalopathies

Diseases caused by prions
Affected animal(s)	Disease
Sheep, Goat	Scrapie^[80]
Cattle	Bovine spongiform encephalopathy^[80]
Camel^[81]	Camel spongiform encephalopathy (CSE)
Mink^[80]	Transmissible mink encephalopathy (TME)
White-tailed deer, elk, mule deer, moose^[80]	Chronic wasting disease (CWD)
Cat^[80]	Feline spongiform encephalopathy (FSE)
Nyala, Oryx, Greater Kudu^[80]	Exotic ungulate encephalopathy (EUE)
Ostrich^[82]	Spongiform encephalopathy (unknown if transmissible)
Human	Creutzfeldt–Jakob disease (CJD)^[80]
	Iatrogenic Creutzfeldt–Jakob disease (iCJD)
	Variant Creutzfeldt–Jakob disease (vCJD)
	Familial Creutzfeldt–Jakob disease (fCJD)
	Sporadic Creutzfeldt–Jakob disease (sCJD)
	Gerstmann–Sträussler–Scheinker syndrome (GSS)^[80]
	Fatal insomnia (FFI)^[83]
	Kuru^[80]
	Familial spongiform encephalopathy^[84]
	Variably protease-sensitive prionopathy (VPSPr)

Prions cause neurodegenerative disease by aggregating extracellularly within the central nervous system to form plaques known as amyloids, which disrupt the normal tissue structure. This disruption is characterized by "holes" in the tissue with resultant spongy architecture due to the vacuole formation in the neurons.^[85] Other histological changes include astrogliosis and the absence of an inflammatory reaction.^[86] While the incubation period for prion diseases is relatively long (5 to 20 years), once symptoms appear the disease progresses rapidly, leading to brain damage and death.^[87] Neurodegenerative symptoms can include convulsions, dementia, ataxia (balance and coordination dysfunction), and behavioural or personality changes.^[88]^[89]

Many different mammalian species can be affected by prion diseases, as the prion protein (PrP) is very similar in all mammals.^[90] Due to small differences in PrP between different species it is unusual for a prion disease to transmit from one species to another. The human prion disease variant Creutzfeldt–Jakob disease, however, is thought to be caused by a prion that typically infects cattle, causing bovine spongiform encephalopathy and is transmitted through infected meat.^[91]

All known prion diseases are untreatable and fatal.^[9]^[92]^[93]

Until 2015 all known mammalian prion diseases were considered to be caused by the prion protein, PrP; in 2015 multiple system atrophy was found to be transmissible and was hypothesized to be caused by a new prion, the misfolded form of a protein called alpha-synuclein.^[10] The endogenous, properly folded form of the prion protein is denoted PrP^C (for Common or Cellular), whereas the disease-linked, misfolded form is denoted PrP^Sc (for Scrapie), after one of the diseases first linked to prions and neurodegeneration.^[36]^[16] The precise structure of the prion is not known, though they can be formed spontaneously by combining PrP^C, homopolymeric polyadenylic acid, and lipids in a protein misfolding cyclic amplification (PMCA) reaction even in the absence of pre-existing infectious prions.^[78] This result is further evidence that prion replication does not require genetic information.^[94]

Transmission

It has been recognized that prion diseases can arise in three different ways: acquired, familial, or sporadic.^[95] It is often assumed that the diseased form directly interacts with the normal form to make it rearrange its structure. One idea, the "Protein X" hypothesis, is that an as-yet unidentified cellular protein (Protein X) enables the conversion of PrP^C to PrP^Sc by bringing a molecule of each of the two together into a complex.^[96]

The primary method of infection in animals is through ingestion. It is thought that prions may be deposited in the environment through the remains of dead animals and via urine, saliva, and other body fluids. They may then linger in the soil by binding to clay and other minerals.^[97]

A University of California research team has provided evidence for the theory that infection can occur from prions in manure.^[98] And, since manure is present in many areas surrounding water reservoirs, as well as used on many crop fields, it raises the possibility of widespread transmission. Although it was initially reported in January 2011 that researchers had discovered prions spreading through airborne transmission on aerosol particles in an animal testing experiment focusing on scrapie infection in laboratory mice,^[99] this report was retracted in 2024.^[100] Preliminary evidence supporting the notion that prions can be transmitted through use of urine-derived human menopausal gonadotropin, administered for the treatment of infertility, was published in 2011.^[101]

Prions in plants

In 2015, researchers at The University of Texas Health Science Center at Houston found that plants can be a vector for prions. When researchers fed hamsters grass that grew on ground where a deer that died with chronic wasting disease (CWD) was buried, the hamsters became ill with CWD, suggesting that prions can bind to plants, which then take them up into the leaf and stem structure, where they can be eaten by herbivores, thus completing the cycle. It is thus possible that there is a progressively accumulating number of prions in the environment.^[102]^[103]

Sterilization

Infectious particles possessing nucleic acid are dependent upon it to direct their continued replication. Prions, however, are infectious by their effect on normal versions of the protein. Sterilizing prions, therefore, requires the denaturation of the protein to a state in which the molecule is no longer able to induce the abnormal folding of normal proteins. In general, prions are quite resistant to proteases, heat, ionizing radiation, and formaldehyde treatments,^[104] although their infectivity can be reduced by such treatments. Effective prion decontamination relies upon protein hydrolysis or reduction or destruction of protein tertiary structure. Examples include sodium hypochlorite, sodium hydroxide, and strongly acidic detergents such as LpH.^[105]

The World Health Organization recommends any of the following three procedures for the sterilization of all heat-resistant surgical instruments to ensure that they are not contaminated with prions:

Immerse in 1N sodium hydroxide and place in a gravity-displacement autoclave at 121 °C for 30 minutes; clean; rinse in water; and then perform routine sterilization processes.
Immerse in 1N sodium hypochlorite (20,000 parts per million available chlorine) for 1 hour; transfer instruments to water; heat in a gravity-displacement autoclave at 121 °C for 1 hour; clean; and then perform routine sterilization processes.
Immerse in 1N sodium hydroxide or sodium hypochlorite (20,000 parts per million available chlorine) for 1 hour; remove and rinse in water, then transfer to an open pan and heat in a gravity-displacement (121 °C) or in a porous-load (134 °C) autoclave for 1 hour; clean; and then perform routine sterilization processes.^[106]

134 °C (273 °F) for 18 minutes in a pressurized steam autoclave has been found to be somewhat effective in deactivating the agent of disease.^[107]^[108] Ozone sterilization is currently being studied as a potential method for prion denaturation and deactivation.^[109] Other approaches being developed include thiourea-urea treatment, guanidinium chloride treatment,^[110] and special heat-resistant subtilisin combined with heat and detergent.^[111] A method sufficient for sterilizing prions on one material may fail on another.^[112]

Renaturation of a completely denatured prion to infectious status has not yet been achieved; however, partially denatured prions can be renatured to an infective status under certain artificial conditions.^[113]

Degradation resistance in nature

Overwhelming evidence shows that prions resist degradation and persist in the environment for years, and proteases do not degrade them. Experimental evidence shows that unbound prions degrade over time, while soil-bound prions remain at stable or increasing levels, suggesting that prions likely accumulate in the environment.^[114]^[115] One 2015 study by US scientists found that repeated drying and wetting may render soil bound prions less infectious, although this was dependent on the soil type they were bound to.^[116]

Degradation by living beings

More recent studies suggest scrapie prions can be degraded by diverse cellular machinery. Inhibition of autophagy accelerates prion accumulation whereas encouragement of autophagy promotes prion clearance.^[117] The ubiquitin proteasome system appears to be able to degrade small enough aggregates.^[117] In addition, keratinase from B. licheniformis,^[118]^[119] alkaline serine protease from Streptomyces sp,^[120] subtilisin-like pernisine from Aeropyrum pernix,^[121] alkaline protease from Nocardiopsis sp,^[122] nattokinase from B. subtilis,^[123] engineered subtilisins from B. lentus^[124]^[125] and serine protease from three lichen species^[126] have been found to degrade PrP.

Fungi

Proteins showing prion-type behavior are also found in some fungi, which has been useful in helping to understand mammalian prions. Fungal prions do not always cause disease in their hosts.^[127] In yeast, protein refolding to the prion configuration is assisted by chaperone proteins such as Hsp104.^[21] All known prions induce the formation of an amyloid fold, in which the protein polymerises into an aggregate consisting of tightly packed beta sheets. Amyloid aggregates are fibrils, growing at their ends, and replicate when breakage causes two growing ends to become four growing ends. The incubation period of prion diseases is determined by the exponential growth rate associated with prion replication, which is a balance between the linear growth and the breakage of aggregates.^[75]

Fungal proteins exhibiting templated conformational change^{[further explanation needed]} were discovered in the yeast Saccharomyces cerevisiae by Reed Wickner in the early 1990s. For their mechanistic similarity to mammalian prions, they were termed yeast prions. Subsequent to this, a prion has also been found in the fungus Podospora anserina. These prions behave similarly to PrP, but, in general, are nontoxic to their hosts. Susan Lindquist's group at the Whitehead Institute has argued some of the fungal prions are not associated with any disease state, but may have a useful role; however, researchers at the NIH have also provided arguments suggesting that fungal prions could be considered a diseased state.^[128] There is evidence that fungal proteins have evolved specific functions that are beneficial to the microorganism that enhance their ability to adapt to their diverse environments.^[129] Further, within yeasts, prions can act as vectors of epigenetic inheritance, transferring traits to offspring without any genomic change.^[130]^[131]

Research into fungal prions has given strong support to the protein-only concept, since purified protein extracted from cells with a prion state has been demonstrated to convert the normal form of the protein into a misfolded form in vitro, and in the process, preserve the information corresponding to different strains of the prion state. It has also shed some light on prion domains, which are regions in a protein that promote the conversion into a prion. Fungal prions have helped to suggest mechanisms of conversion that may apply to all prions, though fungal prions appear distinct from infectious mammalian prions in the lack of cofactor required for propagation. The characteristic prion domains may vary between species – e.g., characteristic fungal prion domains are not found in mammalian prions.^{[citation needed]}

Fungal prions
Protein	Natural host	Normal function	Prion state	Prion phenotype	Year identified
Ure2p	Saccharomyces cerevisiae	Nitrogen catabolite repressor	[URE3]	Growth on poor nitrogen sources	1994
Sup35p	S. cerevisiae	Translation termination factor	[PSI+]	Increased levels of nonsense suppression	1994
HET-S	Podospora anserina	Regulates heterokaryon incompatibility	[Het-s]	Heterokaryon formation between incompatible strains
Rnq1p	S. cerevisiae	Protein template factor	[RNQ+], [PIN+]	Promotes aggregation of other prions
Swi1	S. cerevisiae	Chromatin remodeling	[SWI+]	Poor growth on some carbon sources	2008
Cyc8	S. cerevisiae	Transcriptional repressor	[OCT+]	Transcriptional derepression of multiple genes	2009
Mot3	S. cerevisiae	Nuclear transcription factor	[MOT3+]	Transcriptional derepression of anaerobic genes	2009
Sfp1	S. cerevisiae	Putative transcription factor	[ISP+]	Antisuppression	2010^[132]^{[contradictory]}

Treatments

There are no effective treatments for prion diseases.^[133] Clinical trials in humans have not met with success and have been hampered by the rarity of prion diseases.^[133] Although some potential treatments have shown promise in the laboratory, none have been effective once the disease has commenced.^[134]

In other diseases

Prion-like domains have been found in a variety of other mammalian proteins. Some of these proteins have been implicated in the ontogeny of age-related neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U), Alzheimer's disease, Parkinson's disease, and Huntington's disease.^[135]^[18]^[17] They are also implicated in some forms of systemic amyloidosis including AA amyloidosis that develops in humans and animals with inflammatory and infectious diseases such as tuberculosis, Crohn's disease, rheumatoid arthritis, and HIV/AIDS. AA amyloidosis, like prion disease, may be transmissible.^[136] This has given rise to the 'prion paradigm', where otherwise harmless proteins can be converted to a pathogenic form by a small number of misfolded, nucleating proteins.^[137]

The definition of a prion-like domain arises from the study of fungal prions. In yeast, prionogenic proteins have a portable prion domain that is both necessary and sufficient for self-templating and protein aggregation. This has been shown by attaching the prion domain to a reporter protein, which then aggregates like a known prion. Similarly, removing the prion domain from a fungal prion protein inhibits prionogenesis. This modular view of prion behaviour has led to the hypothesis that similar prion domains are present in animal proteins, in addition to PrP.^[135] These fungal prion domains have several characteristic sequence features. They are typically enriched in asparagine, glutamine, tyrosine and glycine residues, with an asparagine bias being particularly conducive to the aggregative property of prions. Historically, prionogenesis has been seen as independent of sequence and only dependent on relative residue content. However, this has been shown to be false, with the spacing of prolines and charged residues having been shown to be critical in amyloid formation.^[20]

Bioinformatic screens have predicted that over 250 human proteins contain prion-like domains (PrLD). These domains are hypothesized to have the same transmissible, amyloidogenic properties of PrP and known fungal proteins. As in yeast, proteins involved in gene expression and RNA binding seem to be particularly enriched in PrLD's, compared to other classes of protein. In particular, 29 of the known 210 proteins with an RNA recognition motif also have a putative prion domain. Meanwhile, several of these RNA-binding proteins have been independently identified as pathogenic in cases of ALS, FTLD-U, Alzheimer's disease, and Huntington's disease.^[138]

Role in neurodegenerative disease

The pathogenicity of prions and proteins with prion-like domains is hypothesized to arise from their self-templating ability and the resulting exponential growth of amyloid fibrils. The presence of amyloid fibrils in patients with degenerative diseases has been well documented. These amyloid fibrils are seen as the result of pathogenic proteins that self-propagate and form highly stable, non-functional aggregates.^[138] While this does not necessarily imply a causal relationship between amyloid and degenerative diseases, the toxicity of certain amyloid forms and the overproduction of amyloid in familial cases of degenerative disorders supports the idea that amyloid formation is generally toxic.^[139]

Specifically, aggregation of TDP-43, an RNA-binding protein, has been found in ALS/MND patients, and mutations in the genes coding for these proteins have been identified in familial cases of ALS/MND. These mutations promote the misfolding of the proteins into a prion-like conformation. The misfolded form of TDP-43 forms cytoplasmic inclusions in affected neurons, and is found depleted in the nucleus. In addition to ALS/MND and FTLD-U, TDP-43 pathology is a feature of many cases of Alzheimer's disease, Parkinson's disease and Huntington's disease. The misfolding of TDP-43 is largely directed by its prion-like domain. This domain is inherently prone to misfolding, while pathological mutations in TDP-43 have been found to increase this propensity to misfold, explaining the presence of these mutations in familial cases of ALS/MND. As in yeast, the prion-like domain of TDP-43 has been shown to be both necessary and sufficient for protein misfolding and aggregation.^[135]

Similarly, pathogenic mutations have been identified in the prion-like domains of heterogeneous nuclear riboproteins hnRNPA2B1 and hnRNPA1 in familial cases of muscle, brain, bone and motor neuron degeneration. The wild-type form of all of these proteins show a tendency to self-assemble into amyloid fibrils, while the pathogenic mutations exacerbate this behaviour and lead to excess accumulation.^[140]

Weaponization

Prions could theoretically be employed as a weaponized agent.^[141]^[142] With potential fatality rates of 100%, prions could be an effective bioweapon, sometimes called a "biochemical weapon", because a prion is a biochemical. An unfavorable aspect is prions' very long incubation periods. Persistent heavy exposure of prions to the intestine might shorten the overall onset.^[143] Another aspect of using prions in warfare is the difficulty of detection and decontamination.^[144]

History

In the 18th and 19th centuries, exportation of sheep from Spain was observed to coincide with a disease called scrapie. This disease caused the affected animals to "lie down, bite at their feet and legs, rub their backs against posts, fail to thrive, stop feeding and finally become lame".^[145] The disease was also observed to have the long incubation period that is a key characteristic of transmissible spongiform encephalopathies (TSEs). Although the cause of scrapie was not known back then, it is probably the first transmissible spongiform encephalopathy to be recorded.^[146]

In the 1950s, Carleton Gajdusek began research which eventually showed that kuru could be transmitted to chimpanzees by what was possibly a new infectious agent, work for which he eventually won the 1976 Nobel prize. During the 1960s, two London-based researchers, radiation biologist Tikvah Alper and biophysicist John Stanley Griffith, developed the hypothesis that the transmissible spongiform encephalopathies are caused by an infectious agent consisting solely of proteins.^[147]^[148] Earlier investigations by E.J. Field into scrapie and kuru had found evidence for the transfer of pathologically inert polysaccharides that only become infectious post-transfer, in the new host.^[149]^[150] Alper and Griffith wanted to account for the discovery that the mysterious infectious agent causing the diseases scrapie and Creutzfeldt–Jakob disease resisted ionizing radiation.^[151] Griffith proposed three ways in which a protein could be a pathogen.^[152]

In the first hypothesis, he suggested that if the protein is the product of a normally suppressed gene, and introducing the protein could induce the gene's expression, that is, wake the dormant gene up, then the result would be a process indistinguishable from replication, as the gene's expression would produce the protein, which would then wake the gene in other cells.^{[citation needed]}

His second hypothesis forms the basis of the modern prion theory, and proposed that an abnormal form of a cellular protein can convert normal proteins of the same type into its abnormal form, thus leading to replication.^{[citation needed]}

His third hypothesis proposed that the agent could be an antibody if the antibody was its own target antigen, as such an antibody would result in more and more antibody being produced against itself. However, Griffith acknowledged that this third hypothesis was unlikely to be true due to the lack of a detectable immune response.^[153]

Francis Crick recognized the potential significance of the Griffith protein-only hypothesis for scrapie propagation in the second edition of his "Central dogma of molecular biology" (1970): While asserting that the flow of sequence information from protein to protein, or from protein to RNA and DNA was "precluded", he noted that Griffith's hypothesis was a potential contradiction (although it was not so promoted by Griffith).^[154] The revised hypothesis was later formulated, in part, to accommodate reverse transcription (which both Howard Temin and David Baltimore discovered in 1970).^[155]

In 1982, Stanley B. Prusiner of the University of California, San Francisco, announced that his team had purified the hypothetical infectious protein, which did not appear to be present in healthy hosts, though they did not manage to isolate the protein until two years after Prusiner's announcement.^[156]^[24] The protein was named a prion, for "proteinacious infectious particle", derived from the words protein and infection. When the prion was discovered, Griffith's first hypothesis, that the protein was the product of a normally silent gene was favored by many. It was subsequently discovered, however, that the same protein exists in normal hosts but in different form.^[157]

Following the discovery of the same protein in different form in uninfected individuals, the specific protein that the prion was composed of was named the prion protein (PrP), and Griffith's second hypothesis that an abnormal form of a host protein can convert other proteins of the same type into its abnormal form, became the dominant theory.^[153] Prusiner was awarded the Nobel Prize in Physiology or Medicine in 1997 for his research into prions.^[158]^[159]

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External links

CDC – US Center for Disease Control and Prevention – information on prion diseases
World Health Organisation – WHO information on prion diseases
The UK BSE Inquiry – Report of the UK public inquiry into BSE and variant CJD
UK Spongiform Encephalopathy Advisory Committee (SEAC)

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@@ Line 1: / Line 1: @@
 {{Short description|Pathogenic type of misfolded protein}}
-{{cs1 config|name-list-style=vanc}}
 {{About||the bird|Prion (bird)|the theoretical subatomic particle|Preon}}
 {{Distinguish|Major prion protein}}
 {{Good article}}
 {{use mdy dates|date=September 2022}}<!--Looks like the preference to me.-->
+{{cs1 config|name-list-style=vanc|display-authors=6}}
 {{Infobox medical condition
 | name = Prion
@@ Line 17: / Line 17: @@
 The word ''prion'' is derived from the term "proteinaceous infectious particle".<ref>{{cite magazine |url=https://www.scientificamerican.com/article/what-is-a-prion-specifica/ |title=What Is a Prion? |magazine=Scientific American |access-date=15 May 2018 |archive-date=16 May 2018 |archive-url=https://web.archive.org/web/20180516174822/https://www.scientificamerican.com/article/what-is-a-prion-specifica/ |url-status=live }}</ref><ref>{{cite encyclopedia |url=https://www.britannica.com/science/prion-infectious-agent |article=Prion infectious agent |title=Encyclopaedia Britannica |access-date=15 May 2018 |archive-date=16 May 2018 |archive-url=https://web.archive.org/web/20180516183206/https://www.britannica.com/science/prion-infectious-agent |url-status=live }}</ref> The hypothesized role of a protein as an infectious agent stands in contrast to all other known infectious agents such as [[viroid]]s, [[virus]]es, [[bacteria]], [[fungi]], and [[parasite]]s, all of which contain [[nucleic acid]]s ([[DNA]], [[RNA]], or both).
-Most prions are twisted [[Protein isoform|isoforms]] of the [[major prion protein]] (PrP), a natural protein whose normal function is uncertain. They are hypothesized as the cause of transmissible spongiform encephalopathies (TSEs),<ref>{{cite journal |vauthors=Prusiner SB |date=June 1991 |title=Molecular biology of prion diseases |journal=Science |volume=252 |issue=5012 |pages=1515–22 |bibcode=1991Sci...252.1515P |doi=10.1126/science.1675487 |pmid=1675487 |s2cid=22417182}}</ref> including [[scrapie]] in sheep, [[chronic wasting disease]] (CWD) in deer, [[bovine spongiform encephalopathy]] (BSE) in cattle (mad cow disease), [[feline spongiform encephalopathy]] (FSE) in felines, and [[Creutzfeldt–Jakob disease]] (CJD) and [[fatal insomnia]] in humans.
+Most prions are twisted [[Protein isoform|isoforms]] of the [[major prion protein]] (PrP), a natural protein whose normal function is uncertain. They are hypothesized as the cause of transmissible spongiform encephalopathies (TSEs),<ref>{{cite journal | vauthors = Prusiner SB | title = Molecular biology of prion diseases | journal = Science | volume = 252 | issue = 5012 | pages = 1515–1522 | date = June 1991 | pmid = 1675487 | doi = 10.1126/science.1675487 | bibcode = 1991Sci...252.1515P | s2cid = 22417182 }}</ref> including [[scrapie]] in sheep, [[chronic wasting disease]] (CWD) in deer, [[bovine spongiform encephalopathy]] (BSE) in cattle (mad cow disease), [[feline spongiform encephalopathy]] (FSE) in felines, and [[Creutzfeldt–Jakob disease]] (CJD) and [[fatal insomnia]] in humans.
-All known prion diseases in [[mammal]]s affect the structure of the [[brain]] or other [[neuron|neural]] tissue; all are progressive, have no known effective treatment, [[List of human disease case fatality rates|and are always fatal]].<ref name=":0">{{cite journal | vauthors = Prusiner SB | title = Prions | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 95 | issue = 23 | pages = 13363–83 | date = November 1998 | pmid = 9811807 | pmc = 33918 | doi = 10.1073/pnas.95.23.13363 | bibcode = 1998PNAS...9513363P | doi-access = free }}</ref> All mammalian prion diseases were believed to be caused by PrP, until 2015, when a prion form of [[alpha-synuclein]] was hypothesized to cause [[multiple system atrophy]] (MSA).<ref name="pmid26324905" />
+All known prion diseases in [[mammal]]s affect the structure of the [[brain]] or other [[neuron|neural]] tissue; all are progressive, have no known effective treatment, [[List of human disease case fatality rates|and are always fatal]].<ref name=":0">{{cite journal | vauthors = Prusiner SB | title = Prions | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 95 | issue = 23 | pages = 13363–13383 | date = November 1998 | pmid = 9811807 | pmc = 33918 | doi = 10.1073/pnas.95.23.13363 | doi-access = free | bibcode = 1998PNAS...9513363P }}</ref> All mammalian prion diseases were believed to be caused by PrP, until 2015, when a prion form of [[alpha-synuclein]] was hypothesized to cause [[multiple system atrophy]] (MSA).<ref name="pmid26324905" />
-Prions are a type of [[intrinsically disordered protein]], which continuously change their conformation unless they are bound to a specific partner such as another protein. With a prion, two protein chains are stabilized if one binds to another in the same conformation. The probability of this happening is low, but once it does, the combination of the two is very stable. Then more units can get added, making a sort of "[[fibril]]".<ref name="Brahic" /> Prions form abnormal aggregates of proteins called [[amyloids]], which accumulate in infected tissue and are associated with tissue damage and cell death.<ref>{{cite journal | vauthors = Dobson CM | title = The structural basis of protein folding and its links with human disease | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 356 | issue = 1406 | pages = 133–45 | date = February 2001 | pmid = 11260793 | pmc = 1088418 | doi = 10.1098/rstb.2000.0758 }}</ref> Amyloids are also associated with several other neurodegenerative diseases such as [[Alzheimer's disease]] and [[Parkinson's disease]].<ref>{{cite journal | vauthors = Golde TE, Borchelt DR, Giasson BI, Lewis J | title = Thinking laterally about neurodegenerative proteinopathies | journal = The Journal of Clinical Investigation | volume = 123 | issue = 5 | pages = 1847–55 | date = May 2013 | pmid = 23635781 | pmc = 3635732 | doi = 10.1172/JCI66029 }}</ref><ref name="pmid18368143">{{cite journal | vauthors = Irvine GB, El-Agnaf OM, Shankar GM, Walsh DM | title = Protein aggregation in the brain: the molecular basis for Alzheimer's and Parkinson's diseases | journal = Molecular Medicine | volume = 14 | issue = 7–8 | pages = 451–64 | year = 2008 | pmid = 18368143 | pmc = 2274891 | doi = 10.2119/2007-00100.Irvine }}</ref>
+Prions are a type of [[intrinsically disordered protein]], which continuously change their conformation unless they are bound to a specific partner such as another protein. With a prion, two protein chains are stabilized if one binds to another in the same conformation. The probability of this happening is low, but once it does, the combination of the two is very stable. Then more units can get added, making a sort of "[[fibril]]".<ref name="Brahic" /> Prions form abnormal aggregates of proteins called [[amyloids]], which accumulate in infected tissue and are associated with tissue damage and cell death.<ref>{{cite journal | vauthors = Dobson CM | title = The structural basis of protein folding and its links with human disease | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 356 | issue = 1406 | pages = 133–145 | date = February 2001 | pmid = 11260793 | pmc = 1088418 | doi = 10.1098/rstb.2000.0758 }}</ref> Amyloids are also associated with several other neurodegenerative diseases such as [[Alzheimer's disease]] and [[Parkinson's disease]].<ref>{{cite journal | vauthors = Golde TE, Borchelt DR, Giasson BI, Lewis J | title = Thinking laterally about neurodegenerative proteinopathies | journal = The Journal of Clinical Investigation | volume = 123 | issue = 5 | pages = 1847–1855 | date = May 2013 | pmid = 23635781 | pmc = 3635732 | doi = 10.1172/JCI66029 }}</ref><ref name="pmid18368143">{{cite journal | vauthors = Irvine GB, El-Agnaf OM, Shankar GM, Walsh DM | title = Protein aggregation in the brain: the molecular basis for Alzheimer's and Parkinson's diseases | journal = Molecular Medicine | volume = 14 | issue = 7-8 | pages = 451–464 | year = 2008 | pmid = 18368143 | pmc = 2274891 | doi = 10.2119/2007-00100.Irvine }}</ref>
-A prion disease is a type of [[proteopathy]], or disease of structurally abnormal proteins. In humans, prions are believed to be the cause of Creutzfeldt–Jakob disease (CJD), [[variant Creutzfeldt–Jakob disease|its variant]] (vCJD), [[Gerstmann–Sträussler–Scheinker syndrome]] (GSS), [[Fatal insomnia|fatal familial insomnia]] (FFI), and [[Kuru (disease)|kuru]].<ref name="Prion Diseases CDC">{{cite web |url=https://www.cdc.gov/prions/index.html |title=Prion diseases |publisher=United States Centers for Disease Control and Prevention |date=2019-05-03 |access-date=2017-09-08 |archive-date=2020-05-18 |archive-url=https://web.archive.org/web/20200518053638/https://www.cdc.gov/prions/index.html |url-status=live }}</ref> There is also evidence suggesting prions may play a part in the process of Alzheimer's disease, Parkinson's disease, and [[amyotrophic lateral sclerosis]] (ALS); these have been termed ''prion-like diseases''.<ref name="pmid19242475">{{cite journal | vauthors = Laurén J, Gimbel DA, Nygaard HB, Gilbert JW, Strittmatter SM | title = Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers | journal = Nature | volume = 457 | issue = 7233 | pages = 1128–32 | date = February 2009 | pmid = 19242475 | pmc = 2748841 | doi = 10.1038/nature07761 | bibcode = 2009Natur.457.1128L }}</ref><ref name="Olanow">{{cite journal | vauthors = Olanow CW, Brundin P | title = Parkinson's disease and alpha synuclein: is Parkinson's disease a prion-like disorder? | journal = Movement Disorders | volume = 28 | issue = 1 | pages = 31–40 | date = January 2013 | pmid = 23390095 | doi = 10.1002/mds.25373 | s2cid = 38287298 }}</ref><ref name="Goedert">{{cite journal | vauthors = Goedert M | s2cid = 206558562 | title = NEURODEGENERATION. Alzheimer's and Parkinson's diseases: The prion concept in relation to assembled Aβ, tau, and α-synuclein | journal = Science | volume = 349 | issue = 6248 | pages = 1255555 | date = August 2015 | pmid = 26250687 | doi = 10.1126/science.1255555 }}</ref><ref>{{cite journal | vauthors = Lee S, Kim HJ | title = Prion-like Mechanism in Amyotrophic Lateral Sclerosis: are Protein Aggregates the Key? | journal = Experimental Neurobiology | volume = 24 | issue = 1 | pages = 1–7 | date = March 2015 | pmid = 25792864 | pmc = 4363329 | doi = 10.5607/en.2015.24.1.1 }}</ref> Several [[yeast]] proteins have also been identified as having prionogenic properties,<ref name="Alberti, 2009" /><ref name="Aguzzi" /> as well as a protein involved in modification of [[synapse]]s during the formation of memories<ref>{{cite journal | vauthors = Si K, Lindquist S, Kandel ER | author2-link = Susan Lindquist | author3-link = Eric Kandel | title = A neuronal isoform of the aplysia CPEB has prion-like properties | journal = Cell | volume = 115 | issue = 7 | pages = 879–891 | date = December 2003 | pmid = 14697205 | doi = 10.1016/S0092-8674(03)01020-1 |s2cid=3060439 | doi-access = free }}</ref><ref name=Brahic>{{cite journal | vauthors = Brahic M |title=The surprising upsides of the prions behind horrifying brain diseases |journal=New Scientist |date=Nov 10, 2021 |url=https://www.newscientist.com/article/mg25233600-700-the-surprising-upsides-of-the-prions-behind-horrifying-brain-diseases/ |access-date=November 13, 2021 |archive-date=November 13, 2021 |archive-url=https://web.archive.org/web/20211113070338/https://www.newscientist.com/article/mg25233600-700-the-surprising-upsides-of-the-prions-behind-horrifying-brain-diseases/ |url-status=live }}</ref> (see {{slink|Eric Kandel|Molecular changes during learning}}). Prion replication is subject to [[epimutation]] and [[natural selection]] just as for other forms of replication, and their structure varies slightly between species.<ref>{{cite journal |vauthors=Li J, Browning S, Mahal SP, Oelschlegel AM, Weissmann C |title=Darwinian evolution of prions in cell culture |journal=Science|volume=327|issue=5967|pages=869–872 |date=31 Dec 2009 |pmid=20044542 |pmc=2848070 |doi=10.1126/science.1183218 |bibcode=2010Sci...327..869L}}<br />Lay summary: {{cite web |title='Lifeless' prion proteins are 'capable of evolution' |url=http://news.bbc.co.uk/2/hi/health/8435320.stm |date=January 1, 2010 |website=BBC News}}</ref>
+A prion disease is a type of [[proteopathy]], or disease of structurally abnormal proteins. In humans, prions are believed to be the cause of Creutzfeldt–Jakob disease (CJD), [[variant Creutzfeldt–Jakob disease|its variant]] (vCJD), [[Gerstmann–Sträussler–Scheinker syndrome]] (GSS), [[Fatal insomnia|fatal familial insomnia]] (FFI), and [[Kuru (disease)|kuru]].<ref name="Prion Diseases CDC">{{cite web |url=https://www.cdc.gov/prions/index.html |title=Prion diseases |publisher=United States Centers for Disease Control and Prevention |date=2019-05-03 |access-date=2017-09-08 |archive-date=2020-05-18 |archive-url=https://web.archive.org/web/20200518053638/https://www.cdc.gov/prions/index.html |url-status=live }}</ref> There is also evidence suggesting prions may play a part in the process of Alzheimer's disease, Parkinson's disease, and [[amyotrophic lateral sclerosis]] (ALS); these have been termed ''prion-like diseases''.<ref name="pmid19242475">{{cite journal | vauthors = Laurén J, Gimbel DA, Nygaard HB, Gilbert JW, Strittmatter SM | title = Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers | journal = Nature | volume = 457 | issue = 7233 | pages = 1128–1132 | date = February 2009 | pmid = 19242475 | pmc = 2748841 | doi = 10.1038/nature07761 | bibcode = 2009Natur.457.1128L }}</ref><ref name="Olanow">{{cite journal | vauthors = Olanow CW, Brundin P | title = Parkinson's disease and alpha synuclein: is Parkinson's disease a prion-like disorder? | journal = Movement Disorders | volume = 28 | issue = 1 | pages = 31–40 | date = January 2013 | pmid = 23390095 | doi = 10.1002/mds.25373 | s2cid = 38287298 }}</ref><ref name="Goedert">{{cite journal | vauthors = Goedert M | title = NEURODEGENERATION. Alzheimer's and Parkinson's diseases: The prion concept in relation to assembled Aβ, tau, and α-synuclein | journal = Science | volume = 349 | issue = 6248 | pages = 1255555 | date = August 2015 | pmid = 26250687 | doi = 10.1126/science.1255555 | s2cid = 206558562 }}</ref><ref>{{cite journal | vauthors = Lee S, Kim HJ | title = Prion-like Mechanism in Amyotrophic Lateral Sclerosis: are Protein Aggregates the Key? | journal = Experimental Neurobiology | volume = 24 | issue = 1 | pages = 1–7 | date = March 2015 | pmid = 25792864 | pmc = 4363329 | doi = 10.5607/en.2015.24.1.1 }}</ref> Several [[yeast]] proteins have also been identified as having prionogenic properties,<ref name="Alberti, 2009" /><ref name="Aguzzi" /> as well as a protein involved in modification of [[synapse]]s during the formation of memories<ref>{{cite journal | vauthors = Si K, Lindquist S, Kandel ER | title = A neuronal isoform of the aplysia CPEB has prion-like properties | journal = Cell | volume = 115 | issue = 7 | pages = 879–891 | date = December 2003 | pmid = 14697205 | doi = 10.1016/S0092-8674(03)01020-1 | s2cid = 3060439 | author3-link = Eric Kandel | doi-access = free | author2-link = Susan Lindquist }}</ref><ref name=Brahic>{{cite journal | vauthors = Brahic M |title=The surprising upsides of the prions behind horrifying brain diseases |journal=New Scientist |date=Nov 10, 2021 |url=https://www.newscientist.com/article/mg25233600-700-the-surprising-upsides-of-the-prions-behind-horrifying-brain-diseases/ |access-date=November 13, 2021 |archive-date=November 13, 2021 |archive-url=https://web.archive.org/web/20211113070338/https://www.newscientist.com/article/mg25233600-700-the-surprising-upsides-of-the-prions-behind-horrifying-brain-diseases/ |url-status=live }}</ref> (see {{slink|Eric Kandel|Molecular changes during learning}}). Prion replication is subject to [[epimutation]] and [[natural selection]] just as for other forms of replication, and their structure varies slightly between species.<ref>{{cite journal | vauthors = Li J, Browning S, Mahal SP, Oelschlegel AM, Weissmann C | title = Darwinian evolution of prions in cell culture | journal = Science | volume = 327 | issue = 5967 | pages = 869–872 | date = February 2010 | pmid = 20044542 | pmc = 2848070 | doi = 10.1126/science.1183218 | bibcode = 2010Sci...327..869L }}<br />Lay summary: {{cite web |title='Lifeless' prion proteins are 'capable of evolution' |url=http://news.bbc.co.uk/2/hi/health/8435320.stm |date=January 1, 2010 |website=BBC News}}</ref>
 Prion aggregates are stable, and this structural stability means that prions are resistant to [[denaturation (biochemistry)|denaturation]] by chemical and physical agents: they cannot be destroyed by ordinary disinfection or cooking. This makes disposal and containment of these particles difficult, and the risk of [[Iatrogenesis|iatrogenic spread]] through medical instruments a growing concern.
 == Etymology and pronunciation ==
-The word ''prion'', coined in 1982 by [[Stanley B. Prusiner]], is derived from '''pro'''tein and '''in'''fection, hence '''prion''',<ref name="Prusiner82" /> and is short for "proteinaceous infectious particle",<ref name=pmid26324905>{{cite journal |vauthors=Prusiner SB, Woerman AL, Mordes DA, Watts JC, Rampersaud R, Berry DB, Patel S, Oehler A, Lowe JK, Kravitz SN, Geschwind DH, Glidden DV, Halliday GM, Middleton LT, Gentleman SM, Grinberg LT, Giles K |title=Evidence for α-synuclein prions causing multiple system atrophy in humans with parkinsonism |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=112 |issue=38 |pages=E5308–17 |date=September 2015 |pmid=26324905 |pmc=4586853 |doi=10.1073/pnas.1514475112 |bibcode=2015PNAS..112E5308P |doi-access=free}}<br />Lay summary: {{cite web | vauthors = Makin S |title=A Red Flag for a Neurodegenerative Disease That May Be Transmissible |url=http://www.scientificamerican.com/article/a-red-flag-for-a-neurodegenerative-disease-that-may-be-transmissible/ |date=September 1, 2015 |website=Scientific American}}</ref> in reference to its ability to self-propagate and transmit its conformation to other proteins.<ref name="Nobel">{{cite web |title=Stanley B. Prusiner – Autobiography |url=http://nobelprize.org/nobel_prizes/medicine/laureates/1997/prusiner-autobio.html |publisher=NobelPrize.org |access-date=2007-01-02 |archive-date=2013-06-16 |archive-url=https://web.archive.org/web/20130616122714/http://www.nobelprize.org/nobel_prizes/medicine/laureates/1997/prusiner-autobio.html |url-status=live}}</ref> Its main pronunciation is {{IPAc-en|audio=Pronunciation prion.ogg|ˈ|p|r|iː|ɒ|n}},<ref>{{cite journal |vauthors=Schonberger LB, Schonberger RB |title=Etymologia: prion |journal=Emerging Infectious Diseases |volume=18 |issue=6 |pages=1030–1031 |date=June 2012 |pmid=22607731 |pmc=3381685 |doi=10.3201/eid1806.120271}}</ref><ref name="Dorlands">{{cite web |title=Dorland's Illustrated Medical Dictionary |publisher=Elsevier |url=http://dorlands.com/ |access-date=2016-07-22 |url-access=subscription |url-status=dead |archive-date=2014-01-11 |archive-url=https://web.archive.org/web/20140111192614/http://dorlands.com/}}</ref><ref name="MWU">{{cite web |title=Merriam-Webster's Unabridged Dictionary |publisher=Merriam-Webster |url=http://unabridged.merriam-webster.com/unabridged/ |access-date=2016-07-22 |archive-date=2020-05-25 |archive-url=https://web.archive.org/web/20200525084504/https://unabridged.merriam-webster.com/subscriber/login?redirect_to=%2Funabridged%2F |url-status=dead |url-access=subscription}}</ref> although {{IPAc-en|ˈ|p|r|aɪ|ɒ|n}}, as the [[homograph]]ic name of [[prion (bird)|the bird]] (prions or whalebirds) is pronounced,<ref name="MWU"/> is also heard.<ref name="AHD">{{cite web |title=The American Heritage Dictionary of the English Language |publisher=Houghton Mifflin Harcourt |url=https://ahdictionary.com/ |access-date=2016-07-22 |url-status=dead |archive-date=2015-09-25 |archive-url=https://web.archive.org/web/20150925104737/https://ahdictionary.com/}}</ref> In his 1982 paper introducing the term, Prusiner specified that it is "pronounced ''pree-on''".<ref name=Prusiner82/>
+The word ''prion'', coined in 1982 by [[Stanley B. Prusiner]], is derived from '''pro'''tein and '''in'''fection, hence '''prion''',<ref name="Prusiner82" /> and is short for "proteinaceous infectious particle",<ref name=pmid26324905>{{cite journal | vauthors = Prusiner SB, Woerman AL, Mordes DA, Watts JC, Rampersaud R, Berry DB, Patel S, Oehler A, Lowe JK, Kravitz SN, Geschwind DH, Glidden DV, Halliday GM, Middleton LT, Gentleman SM, Grinberg LT, Giles K | title = Evidence for α-synuclein prions causing multiple system atrophy in humans with parkinsonism | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 112 | issue = 38 | pages = E5308-E5317 | date = September 2015 | pmid = 26324905 | pmc = 4586853 | doi = 10.1073/pnas.1514475112 | doi-access = free | bibcode = 2015PNAS..112E5308P }}<br />Lay summary: {{cite web | vauthors = Makin S |title=A Red Flag for a Neurodegenerative Disease That May Be Transmissible |url=http://www.scientificamerican.com/article/a-red-flag-for-a-neurodegenerative-disease-that-may-be-transmissible/ |date=September 1, 2015 |website=Scientific American}}</ref> in reference to its ability to self-propagate and transmit its conformation to other proteins.<ref name="Nobel">{{cite web |title=Stanley B. Prusiner – Autobiography |url=http://nobelprize.org/nobel_prizes/medicine/laureates/1997/prusiner-autobio.html |publisher=NobelPrize.org |access-date=2007-01-02 |archive-date=2013-06-16 |archive-url=https://web.archive.org/web/20130616122714/http://www.nobelprize.org/nobel_prizes/medicine/laureates/1997/prusiner-autobio.html |url-status=live}}</ref> Its main pronunciation is {{IPAc-en|audio=Pronunciation prion.ogg|ˈ|p|r|iː|ɒ|n}},<ref>{{cite journal | vauthors = Schonberger LB, Schonberger RB | title = Etymologia: prion | journal = Emerging Infectious Diseases | volume = 18 | issue = 6 | pages = 1030–1031 | date = June 2012 | pmid = 22607731 | pmc = 3381685 | doi = 10.3201/eid1806.120271 }}</ref><ref name="Dorlands">{{cite web |title=Dorland's Illustrated Medical Dictionary |publisher=Elsevier |url=http://dorlands.com/ |access-date=2016-07-22 |url-access=subscription |url-status=dead |archive-date=2014-01-11 |archive-url=https://web.archive.org/web/20140111192614/http://dorlands.com/}}</ref><ref name="MWU">{{cite web |title=Merriam-Webster's Unabridged Dictionary |publisher=Merriam-Webster |url=http://unabridged.merriam-webster.com/unabridged/ |access-date=2016-07-22 |archive-date=2020-05-25 |archive-url=https://web.archive.org/web/20200525084504/https://unabridged.merriam-webster.com/subscriber/login?redirect_to=%2Funabridged%2F |url-status=dead |url-access=subscription}}</ref> although {{IPAc-en|ˈ|p|r|aɪ|ɒ|n}}, as the [[homograph]]ic name of [[prion (bird)|the bird]] (prions or whalebirds) is pronounced,<ref name="MWU"/> is also heard.<ref name="AHD">{{cite web |title=The American Heritage Dictionary of the English Language |publisher=Houghton Mifflin Harcourt |url=https://ahdictionary.com/ |access-date=2016-07-22 |url-status=dead |archive-date=2015-09-25 |archive-url=https://web.archive.org/web/20150925104737/https://ahdictionary.com/}}</ref> In his 1982 paper introducing the term, Prusiner specified that it is "pronounced ''pree-on''".<ref name=Prusiner82/>
 == Prion protein ==
@@ Line 36: / Line 36: @@
 {{Further|Major prion protein#Structure}}
-Prions consist of a misfolded form of [[major prion protein]] (PrP), a protein that is a natural part of the bodies of humans and other animals. The PrP found in infectious prions has a different [[Protein structure|structure]] and is resistant to [[protease]]s, the enzymes in the body that can normally break down proteins. The normal form of the protein is called PrP<sup>C</sup>, while the infectious form is called PrP<sup>Sc</sup>&nbsp;– the ''C'' refers to 'cellular' PrP, while the ''Sc'' refers to '[[scrapie]]', the prototypic prion disease, occurring in sheep.<ref name="sci5621">{{cite journal |vauthors=Priola SA, Chesebro B, Caughey B |s2cid=38459669 |title=Biomedicine. A view from the top – prion diseases from 10,000 feet |journal=Science |volume=300 |issue=5621 |pages=917–919 |date=May 2003 |pmid=12738843 |doi=10.1126/science.1085920 |url=https://zenodo.org/record/1230830 |access-date=2020-07-28 |archive-date=2020-07-28 |archive-url=https://web.archive.org/web/20200728140633/https://zenodo.org/record/1230830 |url-status=live}}</ref> PrP can also be induced to fold into other more-or-less well-defined isoforms in vitro; although their relationships to the form(s) that are pathogenic in vivo is often unclear, high-resolution structural analyses have begun to reveal structural features that correlate with prion infectivity.<ref>{{Cite journal |last1=Artikis |first1=Efrosini |last2=Kraus |first2=Allison |last3=Caughey |first3=Byron |date=August 2022 |title=Structural biology of ex vivo mammalian prions |journal=Journal of Biological Chemistry |language=en |volume=298 |issue=8 |pages=102181 |doi=10.1016/j.jbc.2022.102181 |doi-access=free |pmc=9293645 |pmid=35752366}}</ref>
+Prions consist of a misfolded form of [[major prion protein]] (PrP), a protein that is a natural part of the bodies of humans and other animals. The PrP found in infectious prions has a different [[Protein structure|structure]] and is resistant to [[protease]]s, the enzymes in the body that can normally break down proteins. The normal form of the protein is called PrP<sup>C</sup>, while the infectious form is called PrP<sup>Sc</sup>&nbsp;– the ''C'' refers to 'cellular' PrP, while the ''Sc'' refers to '[[scrapie]]', the prototypic prion disease, occurring in sheep.<ref name="sci5621">{{cite journal | vauthors = Priola SA, Chesebro B, Caughey B | title = Biomedicine. A view from the top--prion diseases from 10,000 feet | journal = Science | volume = 300 | issue = 5621 | pages = 917–919 | date = May 2003 | pmid = 12738843 | doi = 10.1126/science.1085920 | url = https://zenodo.org/record/1230830 | access-date = 2020-07-28 | url-status = live | s2cid = 38459669 | archive-url = https://web.archive.org/web/20200728140633/https://zenodo.org/record/1230830 | archive-date = 2020-07-28 }}</ref> PrP can also be induced to fold into other more-or-less well-defined isoforms in vitro; although their relationships to the form(s) that are pathogenic in vivo is often unclear, high-resolution structural analyses have begun to reveal structural features that correlate with prion infectivity.<ref>{{cite journal | vauthors = Artikis E, Kraus A, Caughey B | title = Structural biology of ex vivo mammalian prions | journal = The Journal of Biological Chemistry | volume = 298 | issue = 8 | pages = 102181 | date = August 2022 | pmid = 35752366 | pmc = 9293645 | doi = 10.1016/j.jbc.2022.102181 | doi-access = free }}</ref>
 ==== PrP<sup>C</sup> ====
-PrP<sup>C</sup> is a normal protein found on the [[cell membrane|membranes]] of [[cell (biology)|cells]], "including several blood components of which [[platelets]] constitute the largest reservoir in humans."<ref name="robertson06">{{cite journal |vauthors=Robertson C, Booth SA, Beniac DR, Coulthart MB, Booth TF, McNicol A |date=15 May 2006 |title=Cellular prion protein is released on exosomes from activated platelets |journal=Blood |volume=107 |issue=10 |pages=3907–3911 |doi=10.1182/blood-2005-02-0802 |pmid=16434486|s2cid=34141310 |doi-access=free }}</ref> It has 209 [[amino acid]]s (in humans), one [[disulfide bond]], a molecular mass of 35–36 [[Atomic mass unit|kDa]] and a mainly [[alpha helix|alpha-helical]] structure.<ref>{{Cite journal |last1=Riek |first1=Roland |last2=Hornemann |first2=Simone |last3=Wider |first3=Gerhard |last4=Glockshuber |first4=Rudi |last5=Wüthrich |first5=Kurt |date=1997-08-18 |title=NMR characterization of the full-length recombinant murine prion protein, m PrP(23–231) |url=https://febs.onlinelibrary.wiley.com/doi/10.1016/S0014-5793%2897%2900920-4 |journal=FEBS Letters |language=en |volume=413 |issue=2 |pages=282–288 |doi=10.1016/S0014-5793(97)00920-4 |pmid=9280298 |bibcode=1997FEBSL.413..282R |s2cid=39791520 |issn=0014-5793}}</ref><ref>{{Cite journal |last1=Donne |first1=David G. |last2=Viles |first2=John H. |last3=Groth |first3=Darlene |last4=Mehlhorn |first4=Ingrid |last5=James |first5=Thomas L. |last6=Cohen |first6=Fred E. |last7=Prusiner |first7=Stanley B. |last8=Wright |first8=Peter E. |last9=Dyson |first9=H. Jane |date=1997-12-09 |title=Structure of the recombinant full-length hamster prion protein PrP(29–231): The N terminus is highly flexible |journal=Proceedings of the National Academy of Sciences |language=en |volume=94 |issue=25 |pages=13452–13457 |doi=10.1073/pnas.94.25.13452 |doi-access=free |pmid=9391046 |pmc=28326 |bibcode=1997PNAS...9413452D |issn=0027-8424}}</ref> Several [[Protein topology|topological]] forms exist; one cell surface form anchored via [[glycolipid]] and two [[transmembrane]] forms.<ref>{{cite journal | vauthors = Hegde RS, Mastrianni JA, Scott MR, DeFea KA, Tremblay P, Torchia M, DeArmond SJ, Prusiner SB, Lingappa VR | s2cid = 20176119 | title = A transmembrane form of the prion protein in neurodegenerative disease | journal = Science | volume = 279 | issue = 5352 | pages = 827–34 | date = February 1998 | pmid = 9452375 | doi = 10.1126/science.279.5352.827 | bibcode = 1998Sci...279..827H | url = http://pdfs.semanticscholar.org/4320/9efc152784dbc7f0b9a1300d0ec9be602a2c.pdf | archive-url = https://web.archive.org/web/20190223062543/http://pdfs.semanticscholar.org/4320/9efc152784dbc7f0b9a1300d0ec9be602a2c.pdf | url-status = dead | archive-date = 2019-02-23 }}</ref> The normal protein is not sedimentable; meaning that it cannot be separated by [[Laboratory centrifuge|centrifuging techniques]].<ref name=Krull>{{cite book | vauthors = Carp RI, Kascap RJ | chapter = Taking aim at the transmissible spongiform encephalopathie's infectious agents | veditors = Krull IS, Nunnally BK | title = Prions and mad cow disease | publisher = Marcel Dekker | location = New York | year = 2004 | page = 6 | isbn = 978-0-8247-4083-2 | chapter-url = https://books.google.com/books?id=WjeuaHopV5UC&pg=PA6 | access-date = 2020-06-02 | archive-date = 2020-08-20 | archive-url = https://web.archive.org/web/20200820011006/https://books.google.com/books?id=WjeuaHopV5UC&pg=PA6 | url-status = live }}</ref> It has a complex [[Protein function|function]], which continues to be investigated. PrP<sup>C</sup> [[Chemical bond|binds]] [[copper]](II) [[ion]]s (those in a +2 [[oxidation state]]) with [[high affinity]].<ref>{{cite journal | vauthors = Brown DR, Qin K, Herms JW, Madlung A, Manson J, Strome R, Fraser PE, Kruck T, von Bohlen A, Schulz-Schaeffer W, Giese A, Westaway D, Kretzschmar H | s2cid = 4388803 | title = The cellular prion protein binds copper in vivo | journal = Nature | volume = 390 | issue = 6661 | pages = 684–87 | year = 1997 | pmid = 9414160 | doi = 10.1038/37783 | bibcode = 1997Natur.390..684B }}</ref> The significance of this property is not clear, but it is presumed{{By whom|date=May 2024}} to relate to the protein's structure or function. PrP<sup>C</sup> is readily [[Digestion|digested]] by [[proteinase K]] and can be [[Exocytosis|liberated]] from the cell surface by the enzyme [[phospholipase C|phosphoinositide phospholipase C]] (PI-PLC), which [[Bond cleavage|cleaves]] the [[glycophosphatidylinositol]] (GPI) glycolipid anchor.<ref name="weissmann">{{cite journal | vauthors = Weissmann C | s2cid = 20992257 | title = The state of the prion | journal = Nature Reviews. Microbiology | volume = 2 | issue = 11 | pages = 861–71 | date = November 2004 | pmid = 15494743 | doi = 10.1038/nrmicro1025 }}</ref> PrP plays an important role in [[cell-cell adhesion]] and [[intracellular signaling]] ''in vivo'',<ref>{{cite journal |vauthors=Málaga-Trillo E, Solis GP, Schrock Y, Geiss C, Luncz L, Thomanetz V, Stuermer CA |date=March 2009 |title=Regulation of embryonic cell adhesion by the prion protein |journal=PLOS Biology |volume=7 |issue=3 |pages=e55 |doi=10.1371/journal.pbio.1000055 |pmc=2653553 |pmid=19278297 |doi-access=free |veditors=Weissmann C}}</ref> and may therefore be involved in cell-cell communication in the brain.<ref>{{Cite journal |last1=Liebert |first1=Ann |last2=Bicknell |first2=Brian |last3=Adams |first3=Roger |date=2014 |title=Prion Protein Signaling in the Nervous System—A Review and Perspective |journal=Signal Transduction Insights |language=en |volume=3 |pages=STI.S12319 |doi=10.4137/STI.S12319 |issn=1178-6434|doi-access=free }}</ref>
+PrP<sup>C</sup> is a normal protein found on the [[cell membrane|membranes]] of [[cell (biology)|cells]], "including several blood components of which [[platelets]] constitute the largest reservoir in humans."<ref name="robertson06">{{cite journal | vauthors = Robertson C, Booth SA, Beniac DR, Coulthart MB, Booth TF, McNicol A | title = Cellular prion protein is released on exosomes from activated platelets | journal = Blood | volume = 107 | issue = 10 | pages = 3907–3911 | date = May 2006 | pmid = 16434486 | doi = 10.1182/blood-2005-02-0802 | s2cid = 34141310 | doi-access = free }}</ref> It has 209 [[amino acid]]s (in humans), one [[disulfide bond]], a molecular mass of 35–36 [[Atomic mass unit|kDa]] and a mainly [[alpha helix|alpha-helical]] structure.<ref>{{cite journal | vauthors = Riek R, Hornemann S, Wider G, Glockshuber R, Wüthrich K | title = NMR characterization of the full-length recombinant murine prion protein, mPrP(23-231) | journal = FEBS Letters | volume = 413 | issue = 2 | pages = 282–288 | date = August 1997 | pmid = 9280298 | doi = 10.1016/S0014-5793(97)00920-4 | s2cid = 39791520 | bibcode = 1997FEBSL.413..282R }}</ref><ref>{{cite journal | vauthors = Donne DG, Viles JH, Groth D, Mehlhorn I, James TL, Cohen FE, Prusiner SB, Wright PE, Dyson HJ | title = Structure of the recombinant full-length hamster prion protein PrP(29-231): the N terminus is highly flexible | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 94 | issue = 25 | pages = 13452–13457 | date = December 1997 | pmid = 9391046 | pmc = 28326 | doi = 10.1073/pnas.94.25.13452 | doi-access = free | bibcode = 1997PNAS...9413452D }}</ref> Several [[Protein topology|topological]] forms exist; one cell surface form anchored via [[glycolipid]] and two [[transmembrane]] forms.<ref>{{cite journal | vauthors = Hegde RS, Mastrianni JA, Scott MR, DeFea KA, Tremblay P, Torchia M, DeArmond SJ, Prusiner SB, Lingappa VR | title = A transmembrane form of the prion protein in neurodegenerative disease | journal = Science | volume = 279 | issue = 5352 | pages = 827–834 | date = February 1998 | pmid = 9452375 | doi = 10.1126/science.279.5352.827 | url = http://pdfs.semanticscholar.org/4320/9efc152784dbc7f0b9a1300d0ec9be602a2c.pdf | url-status = dead | s2cid = 20176119 | bibcode = 1998Sci...279..827H | archive-url = https://web.archive.org/web/20190223062543/http://pdfs.semanticscholar.org/4320/9efc152784dbc7f0b9a1300d0ec9be602a2c.pdf | archive-date = 2019-02-23 }}</ref> The normal protein is not sedimentable; meaning that it cannot be separated by [[Laboratory centrifuge|centrifuging techniques]].<ref name=Krull>{{cite book | vauthors = Carp RI, Kascap RJ | chapter = Taking aim at the transmissible spongiform encephalopathie's infectious agents | veditors = Krull IS, Nunnally BK | title = Prions and mad cow disease | publisher = Marcel Dekker | location = New York | year = 2004 | page = 6 | isbn = 978-0-8247-4083-2 | chapter-url = https://books.google.com/books?id=WjeuaHopV5UC&pg=PA6 | access-date = 2020-06-02 | archive-date = 2020-08-20 | archive-url = https://web.archive.org/web/20200820011006/https://books.google.com/books?id=WjeuaHopV5UC&pg=PA6 | url-status = live }}</ref> It has a complex [[Protein function|function]], which continues to be investigated. PrP<sup>C</sup> [[Chemical bond|binds]] [[copper]](II) [[ion]]s (those in a +2 [[oxidation state]]) with [[high affinity]].<ref>{{cite journal | vauthors = Brown DR, Qin K, Herms JW, Madlung A, Manson J, Strome R, Fraser PE, Kruck T, von Bohlen A, Schulz-Schaeffer W, Giese A, Westaway D, Kretzschmar H | title = The cellular prion protein binds copper in vivo | journal = Nature | volume = 390 | issue = 6661 | pages = 684–687 | year = 1997 | pmid = 9414160 | doi = 10.1038/37783 | s2cid = 4388803 | bibcode = 1997Natur.390..684B }}</ref> The significance of this property is not clear, but it is presumed{{By whom|date=May 2024}} to relate to the protein's structure or function. PrP<sup>C</sup> is readily [[Digestion|digested]] by [[proteinase K]] and can be [[Exocytosis|liberated]] from the cell surface by the enzyme [[phospholipase C|phosphoinositide phospholipase C]] (PI-PLC), which [[Bond cleavage|cleaves]] the [[glycophosphatidylinositol]] (GPI) glycolipid anchor.<ref name="weissmann">{{cite journal | vauthors = Weissmann C | title = The state of the prion | journal = Nature Reviews. Microbiology | volume = 2 | issue = 11 | pages = 861–871 | date = November 2004 | pmid = 15494743 | doi = 10.1038/nrmicro1025 | s2cid = 20992257 }}</ref> PrP plays an important role in [[cell-cell adhesion]] and [[intracellular signaling]] ''in vivo'',<ref>{{cite journal | vauthors = Málaga-Trillo E, Solis GP, Schrock Y, Geiss C, Luncz L, Thomanetz V, Stuermer CA | title = Regulation of embryonic cell adhesion by the prion protein | journal = PLoS Biology | volume = 7 | issue = 3 | pages = e55 | date = March 2009 | pmid = 19278297 | pmc = 2653553 | doi = 10.1371/journal.pbio.1000055 | veditors = Weissmann C | doi-access = free }}</ref> and may therefore be involved in cell-cell communication in the brain.<ref>{{Cite journal | vauthors =  Liebert A, Bicknell B, Adams R |date=2014 |title=Prion Protein Signaling in the Nervous System—A Review and Perspective |journal=Signal Transduction Insights |language=en |volume=3 |pages=STI.S12319 |doi=10.4137/STI.S12319 |issn=1178-6434|doi-access=free }}</ref>
 ==== PrP<sup>Sc</sup> ====
 [[File:Scrapie prions.jpg|alt=Photomicrograph of mouse neurons showing red stained inclusions identified as scrapies prion protein.|thumb|upright=0.8|PrP<sup>Sc</sup> (stained in red) revealed in a photomicrograph of scrapie-infected mouse neuronal cells.]]
-The infectious [[isoform]] of PrP, known as PrP<sup>Sc</sup>, or simply the prion, is able to convert normal PrP<sup>C</sup> proteins into the infectious isoform by changing their [[Protein structure|conformation]], or shape; this, in turn, alters the way the proteins [[Protein–protein interaction|interconnect]]. PrP<sup>Sc</sup> always causes prion disease. PrP<sup>Sc</sup> has a higher proportion of [[beta sheet|β-sheet]] structure in place of the normal [[alpha helix|α-helix]] structure.<ref>{{cite journal | vauthors = Caughey B, Dong A, Bhat K, Ernst D, Hayes S, Caughey W | title = Secondary structure analysis of the scrapie-associated protein PrP 27-30 in water by infrared spectroscopy | journal = Biochemistry | volume = 30 | issue = 31 | pages = 7672–80 | date = August 1991 | pmid = 1678278 | doi = 10.1021/bi00245a003 }}</ref><ref>{{Cite journal |last1=Safar |first1=J |last2=Roller |first2=P.P. |last3=Gajdusek |first3=D.C. |last4=Gibbs |first4=C.J. |date=September 1993 |title=Conformational transitions, dissociation, and unfolding of scrapie amyloid (prion) protein. |journal=Journal of Biological Chemistry |volume=268 |issue=27 |pages=20276–20284 |doi=10.1016/s0021-9258(20)80725-x |pmid=8104185 |issn=0021-9258|doi-access=free }}</ref><ref>{{cite journal | vauthors = Pan KM, Baldwin M, Nguyen J, Gasset M, Serban A, Groth D, Mehlhorn I, Huang Z, Fletterick RJ, Cohen FE | title = Conversion of alpha-helices into beta-sheets features in the formation of the scrapie prion proteins | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 90 | issue = 23 | pages = 10962–66 | date = December 1993 | pmid = 7902575 | pmc = 47901 | doi = 10.1073/pnas.90.23.10962 | bibcode = 1993PNAS...9010962P | doi-access = free }}</ref> Several highly infectious, brain-derived PrP<sup>Sc</sup> structures have been discovered by [[cryo-electron microscopy]].<ref>{{cite journal | vauthors = Kraus A, Hoyt F, Schwartz C, Hansen B, Artikis E, Hughson A, Raymond G, Race B, Baron G, Caughey B | title = High-resolution structure and strain comparison of infectious mammalian prions | journal = Molecular Cell | volume = 81 | issue = 21 | pages = 4540–4551 | date = November 2021 | pmid = 34433091 | doi = 10.1016/j.molcel.2021.08.011 }}</ref><ref>{{cite journal | vauthors = Hoyt F, Standke HG, Artikis E, Schwartz CL, Hansen B, Li K, Hughson AG, Manca M, Thomas OR, Raymond GJ, Race B, Baron GS, Caughey B, Kraus A  | title = Cryo-EM structure of anchorless RML prion reveals variations in shared motifs between distinct strains | journal = Nature Communications | volume = 13 | pages = 4005 | date = July 2022 | issue = 1 | pmid = 35831291  | doi = 10.1038/s41467-022-30458-6 | pmc = 9279418 | bibcode = 2022NatCo..13.4005H }}</ref><ref>{{Cite journal |last1=Manka |first1=Szymon W. |last2=Zhang |first2=Wenjuan |last3=Wenborn |first3=Adam |last4=Betts |first4=Jemma |last5=Joiner |first5=Susan |last6=Saibil |first6=Helen R. |last7=Collinge |first7=John |last8=Wadsworth |first8=Jonathan D. F. |date=2022-07-13 |title=2.7 Å cryo-EM structure of ex vivo RML prion fibrils |journal=Nature Communications |language=en |volume=13 |issue=1 |page=4004 |doi=10.1038/s41467-022-30457-7 |issn=2041-1723 |pmc=9279362 |pmid=35831275|bibcode=2022NatCo..13.4004M }}</ref> Another brain-derived [[fibril]] structure isolated from humans with [[Gerstmann–Sträussler–Scheinker syndrome|Gerstmann-Straussler-Schienker syndrome]] has also been determined.<ref>{{Cite journal |last1=Hallinan |first1=Grace I. |last2=Ozcan |first2=Kadir A. |last3=Hoq |first3=Md Rejaul |last4=Cracco |first4=Laura |last5=Vago |first5=Frank S. |last6=Bharath |first6=Sakshibeedu R. |last7=Li |first7=Daoyi |last8=Jacobsen |first8=Max |last9=Doud |first9=Emma H. |last10=Mosley |first10=Amber L. |last11=Fernandez |first11=Anllely |last12=Garringer |first12=Holly J. |last13=Jiang |first13=Wen |last14=Ghetti |first14=Bernardino |last15=Vidal |first15=Ruben |date=September 2022 |title=Cryo-EM structures of prion protein filaments from Gerstmann–Sträussler–Scheinker disease |journal=Acta Neuropathologica |language=en |volume=144 |issue=3 |pages=509–520 |doi=10.1007/s00401-022-02461-0 |issn=0001-6322 |pmc=9381446 |pmid=35819518}}</ref> All of the structures described in high resolution so far are [[amyloid]] fibers in which individual PrP molecules are stacked via intermolecular beta sheets. However, 2-D [[Crystalline form|crystalline arrays]] have also been reported at lower resolution in ''ex vivo'' preparations of prions.<ref>{{Cite journal |last1=Wille |first1=Holger |last2=Michelitsch |first2=Melissa D. |last3=Guénebaut |first3=Vincent |last4=Supattapone |first4=Surachai |last5=Serban |first5=Ana |last6=Cohen |first6=Fred E. |last7=Agard |first7=David A. |last8=Prusiner |first8=Stanley B. |date=2002-03-19 |title=Structural studies of the scrapie prion protein by electron crystallography |journal=Proceedings of the National Academy of Sciences |language=en |volume=99 |issue=6 |pages=3563–3568 |doi=10.1073/pnas.052703499 |doi-access=free |issn=0027-8424 |pmc=122563 |pmid=11891310|bibcode=2002PNAS...99.3563W }}</ref> In the prion amyloids, the [[glycolipid]] anchors and [[asparagine]]-linked glycans, when present, project outward from the lateral surfaces of the fiber cores. Often PrP<sup>Sc</sup> is bound to cellular membranes, presumably via its array of glycolipid anchors, however, sometimes the fibers are dissociated from membranes and accumulate outside of cells in the form of plaques. The end of each fiber acts as a template onto which free protein molecules may attach, allowing the fiber to grow. This growth process requires complete refolding of PrP<sup>C</sup>.<ref>{{Cite journal |last1=Kraus |first1=Allison |last2=Hoyt |first2=Forrest |last3=Schwartz |first3=Cindi L. |last4=Hansen |first4=Bryan |last5=Artikis |first5=Efrosini |last6=Hughson |first6=Andrew G. |last7=Raymond |first7=Gregory J. |last8=Race |first8=Brent |last9=Baron |first9=Gerald S. |last10=Caughey |first10=Byron |date=November 2021 |title=High-resolution structure and strain comparison of infectious mammalian prions |url=https://linkinghub.elsevier.com/retrieve/pii/S1097276521006511 |journal=Molecular Cell |language=en |volume=81 |issue=21 |pages=4540–4551.e6 |doi=10.1016/j.molcel.2021.08.011|pmid=34433091 }}</ref> Different prion strains have distinct templates, or conformations, even when composed of PrP molecules of the same [[amino acid sequence]], as occurs in a particular host [[genotype]].<ref>{{cite journal | vauthors = Bessen RA, Kocisko DA, Raymond GJ, Nandan S, Lansbury PT, Caughey B | title = Non-genetic propagation of strain-specific properties of scrapie prion protein | journal = Nature | volume = 375 | pages = 698–700 | date = June 1995 | issue = 6533 | pmid = 7791905 | doi = 10.1038/375698a0 | bibcode = 1995Natur.375..698B | s2cid = 4355092 }}</ref><ref>{{Cite journal |last1=Telling |first1=Glenn C. |last2=Parchi |first2=Piero |last3=DeArmond |first3=Stephen J. |last4=Cortelli |first4=Pietro |last5=Montagna |first5=Pasquale |last6=Gabizon |first6=Ruth |last7=Mastrianni |first7=James |last8=Lugaresi |first8=Elio |last9=Gambetti |first9=Pierluigi |last10=Prusiner |first10=Stanley B. |date=1996-12-20 |title=Evidence for the Conformation of the Pathologic Isoform of the Prion Protein Enciphering and Propagating Prion Diversity |url=https://www.science.org/doi/10.1126/science.274.5295.2079 |journal=Science |language=en |volume=274 |issue=5295 |pages=2079–2082 |doi=10.1126/science.274.5295.2079 |pmid=8953038 |bibcode=1996Sci...274.2079T |issn=0036-8075}}</ref><ref>{{Cite journal |last1=Safar |first1=Jiri |last2=Wille |first2=Holger |last3=Itri |first3=Vincenza |last4=Groth |first4=Darlene |last5=Serban |first5=Hana |last6=Torchia |first6=Marilyn |last7=Cohen |first7=Fred E. |last8=Prusiner |first8=Stanley B. |date=October 1998 |title=Eight prion strains have PrPSc molecules with different conformations |url=https://www.nature.com/articles/nm1098_1157 |journal=Nature Medicine |language=en |volume=4 |issue=10 |pages=1157–1165 |doi=10.1038/2654 |pmid=9771749 |s2cid=6031488 |issn=1078-8956}}</ref><ref>{{cite journal | vauthors = Hoyt F, Alam P, Artikis E, Schwartz CL, Hughson AG, Race B, Baune C, Raymond GJ, Baron GS, Kraus A, Caughey B | title = Cryo-EM of prion strains from the same genotype of host identifies conformational determinants | journal = PLOS Pathogens | volume = 18 | pages = e1010947 | date = November 2022 | issue = 11 | pmid = 36342968| doi = 10.1371/journal.ppat.1010947 | doi-access = free | pmc = 9671466 }}</ref><ref>{{cite journal | vauthors = Manka SW, Wenborn A, Betts J, Joiner S, Saibil HR, Collinge J, Wadsworth JD | title = A structural basis for prion strain diversity | journal = Nature Chemical Biology | volume = 19 | pages = 607–613| date = May 2023 | issue = 5 | pmid = 36646960| doi = 10.1038/s41589-022-01229-7 | pmc = 10154210 }}</ref> Under most circumstances, only PrP molecules with an identical amino acid sequence to the infectious PrP<sup>Sc</sup> are incorporated into the growing fiber.<ref name=Krull /> However, [[cross-species transmission]] also happens rarely.<ref name="pmid26809254">{{cite journal |vauthors=Kurt TD, Sigurdson CJ |title=Cross-species transmission of CWD prions |journal=Prion |volume=10 |issue=1 |pages=83–91 |date=2016 |pmid=26809254 |pmc=4981193 |doi=10.1080/19336896.2015.1118603 }}</ref>
+The infectious [[isoform]] of PrP, known as PrP<sup>Sc</sup>, or simply the prion, is able to convert normal PrP<sup>C</sup> proteins into the infectious isoform by changing their [[Protein structure|conformation]], or shape; this, in turn, alters the way the proteins [[Protein–protein interaction|interconnect]]. PrP<sup>Sc</sup> always causes prion disease. PrP<sup>Sc</sup> has a higher proportion of [[beta sheet|β-sheet]] structure in place of the normal [[alpha helix|α-helix]] structure.<ref>{{cite journal | vauthors = Caughey BW, Dong A, Bhat KS, Ernst D, Hayes SF, Caughey WS | title = Secondary structure analysis of the scrapie-associated protein PrP 27-30 in water by infrared spectroscopy | journal = Biochemistry | volume = 30 | issue = 31 | pages = 7672–7680 | date = August 1991 | pmid = 1678278 | doi = 10.1021/bi00245a003 }}</ref><ref>{{cite journal | vauthors = Safar J, Roller PP, Gajdusek DC, Gibbs CJ | title = Conformational transitions, dissociation, and unfolding of scrapie amyloid (prion) protein | journal = The Journal of Biological Chemistry | volume = 268 | issue = 27 | pages = 20276–20284 | date = September 1993 | pmid = 8104185 | doi = 10.1016/s0021-9258(20)80725-x | doi-access = free }}</ref><ref>{{cite journal | vauthors = Pan KM, Baldwin M, Nguyen J, Gasset M, Serban A, Groth D, Mehlhorn I, Huang Z, Fletterick RJ, Cohen FE | title = Conversion of alpha-helices into beta-sheets features in the formation of the scrapie prion proteins | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 90 | issue = 23 | pages = 10962–10966 | date = December 1993 | pmid = 7902575 | pmc = 47901 | doi = 10.1073/pnas.90.23.10962 | doi-access = free | bibcode = 1993PNAS...9010962P }}</ref> Several highly infectious, brain-derived PrP<sup>Sc</sup> structures have been discovered by [[cryo-electron microscopy]].<ref>{{cite journal | vauthors = Kraus A, Hoyt F, Schwartz CL, Hansen B, Artikis E, Hughson AG, Raymond GJ, Race B, Baron GS, Caughey B | title = High-resolution structure and strain comparison of infectious mammalian prions | journal = Molecular Cell | volume = 81 | issue = 21 | pages = 4540–4551.e6 | date = November 2021 | pmid = 34433091 | doi = 10.1016/j.molcel.2021.08.011 }}</ref><ref>{{cite journal | vauthors = Hoyt F, Standke HG, Artikis E, Schwartz CL, Hansen B, Li K, Hughson AG, Manca M, Thomas OR, Raymond GJ, Race B, Baron GS, Caughey B, Kraus A | title = Cryo-EM structure of anchorless RML prion reveals variations in shared motifs between distinct strains | journal = Nature Communications | volume = 13 | issue = 1 | pages = 4005 | date = July 2022 | pmid = 35831291 | pmc = 9279418 | doi = 10.1038/s41467-022-30458-6 | bibcode = 2022NatCo..13.4005H }}</ref><ref>{{cite journal | vauthors = Manka SW, Zhang W, Wenborn A, Betts J, Joiner S, Saibil HR, Collinge J, Wadsworth JD | title = 2.7 Å cryo-EM structure of ex vivo RML prion fibrils | journal = Nature Communications | volume = 13 | issue = 1 | pages = 4004 | date = July 2022 | pmid = 35831275 | pmc = 9279362 | doi = 10.1038/s41467-022-30457-7 | bibcode = 2022NatCo..13.4004M }}</ref> Another brain-derived [[fibril]] structure isolated from humans with [[Gerstmann–Sträussler–Scheinker syndrome|Gerstmann-Straussler-Schienker syndrome]] has also been determined.<ref>{{cite journal | vauthors = Hallinan GI, Ozcan KA, Hoq MR, Cracco L, Vago FS, Bharath SR, Li D, Jacobsen M, Doud EH, Mosley AL, Fernandez A, Garringer HJ, Jiang W, Ghetti B, Vidal R | title = Cryo-EM structures of prion protein filaments from Gerstmann-Sträussler-Scheinker disease | journal = Acta Neuropathologica | volume = 144 | issue = 3 | pages = 509–520 | date = September 2022 | pmid = 35819518 | pmc = 9381446 | doi = 10.1007/s00401-022-02461-0 }}</ref> All of the structures described in high resolution so far are [[amyloid]] fibers in which individual PrP molecules are stacked via intermolecular beta sheets. However, 2-D [[Crystalline form|crystalline arrays]] have also been reported at lower resolution in ''ex vivo'' preparations of prions.<ref>{{cite journal | vauthors = Wille H, Michelitsch MD, Guenebaut V, Supattapone S, Serban A, Cohen FE, Agard DA, Prusiner SB | title = Structural studies of the scrapie prion protein by electron crystallography | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 6 | pages = 3563–3568 | date = March 2002 | pmid = 11891310 | pmc = 122563 | doi = 10.1073/pnas.052703499 | doi-access = free | bibcode = 2002PNAS...99.3563W }}</ref> In the prion amyloids, the [[glycolipid]] anchors and [[asparagine]]-linked glycans, when present, project outward from the lateral surfaces of the fiber cores. Often PrP<sup>Sc</sup> is bound to cellular membranes, presumably via its array of glycolipid anchors, however, sometimes the fibers are dissociated from membranes and accumulate outside of cells in the form of plaques. The end of each fiber acts as a template onto which free protein molecules may attach, allowing the fiber to grow. This growth process requires complete refolding of PrP<sup>C</sup>.<ref>{{cite journal | vauthors = Kraus A, Hoyt F, Schwartz CL, Hansen B, Artikis E, Hughson AG, Raymond GJ, Race B, Baron GS, Caughey B | title = High-resolution structure and strain comparison of infectious mammalian prions | journal = Molecular Cell | volume = 81 | issue = 21 | pages = 4540–4551.e6 | date = November 2021 | pmid = 34433091 | doi = 10.1016/j.molcel.2021.08.011 }}</ref> Different prion strains have distinct templates, or conformations, even when composed of PrP molecules of the same [[amino acid sequence]], as occurs in a particular host [[genotype]].<ref>{{cite journal | vauthors = Bessen RA, Kocisko DA, Raymond GJ, Nandan S, Lansbury PT, Caughey B | title = Non-genetic propagation of strain-specific properties of scrapie prion protein | journal = Nature | volume = 375 | issue = 6533 | pages = 698–700 | date = June 1995 | pmid = 7791905 | doi = 10.1038/375698a0 | s2cid = 4355092 | bibcode = 1995Natur.375..698B }}</ref><ref>{{cite journal | vauthors = Telling GC, Parchi P, DeArmond SJ, Cortelli P, Montagna P, Gabizon R, Mastrianni J, Lugaresi E, Gambetti P, Prusiner SB | title = Evidence for the conformation of the pathologic isoform of the prion protein enciphering and propagating prion diversity | journal = Science | volume = 274 | issue = 5295 | pages = 2079–2082 | date = December 1996 | pmid = 8953038 | doi = 10.1126/science.274.5295.2079 | bibcode = 1996Sci...274.2079T }}</ref><ref>{{cite journal | vauthors = Safar J, Wille H, Itri V, Groth D, Serban H, Torchia M, Cohen FE, Prusiner SB | title = Eight prion strains have PrP(Sc) molecules with different conformations | journal = Nature Medicine | volume = 4 | issue = 10 | pages = 1157–1165 | date = October 1998 | pmid = 9771749 | doi = 10.1038/2654 | s2cid = 6031488 }}</ref><ref>{{cite journal | vauthors = Hoyt F, Alam P, Artikis E, Schwartz CL, Hughson AG, Race B, Baune C, Raymond GJ, Baron GS, Kraus A, Caughey B | title = Cryo-EM of prion strains from the same genotype of host identifies conformational determinants | journal = PLoS Pathogens | volume = 18 | issue = 11 | pages = e1010947 | date = November 2022 | pmid = 36342968 | pmc = 9671466 | doi = 10.1371/journal.ppat.1010947 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Manka SW, Wenborn A, Betts J, Joiner S, Saibil HR, Collinge J, Wadsworth JD | title = A structural basis for prion strain diversity | journal = Nature Chemical Biology | volume = 19 | issue = 5 | pages = 607–613 | date = May 2023 | pmid = 36646960 | pmc = 10154210 | doi = 10.1038/s41589-022-01229-7 }}</ref> Under most circumstances, only PrP molecules with an identical amino acid sequence to the infectious PrP<sup>Sc</sup> are incorporated into the growing fiber.<ref name=Krull /> However, [[cross-species transmission]] also happens rarely.<ref name="pmid26809254">{{cite journal | vauthors = Kurt TD, Sigurdson CJ | title = Cross-species transmission of CWD prions | journal = Prion | volume = 10 | issue = 1 | pages = 83–91 | date = 2016 | pmid = 26809254 | pmc = 4981193 | doi = 10.1080/19336896.2015.1118603 }}</ref>
 ==== PrP<sup>res</sup> ====
-Protease-resistant PrP<sup>Sc</sup>-like protein (PrP<sup>res</sup>) is the name given to any isoform of PrP<sup>c</sup> which is structurally altered and converted into a misfolded [[proteinase K]]-resistant form.<ref>{{cite journal |vauthors=Riesner D |date=2003-06-01 |title=Biochemistry and structure of PrP(C) and PrP(Sc) |journal=British Medical Bulletin |volume=66 |issue=1 |pages=21–33 |doi=10.1093/bmb/66.1.21 |pmid=14522846 |doi-access=free}}</ref> To model conversion of PrP<sup>C</sup> to PrP<sup>Sc</sup> ''in vitro'', Kocisko ''et al''. showed that PrP<sup>Sc</sup> could cause PrP<sup>C</sup> to convert to PrP<sup>res</sup> under cell-free conditions <ref name="pmid7913989">{{cite journal |vauthors=Kocisko D, Come J, Priola S, Chesebro B, Raymond G, Lansbury P, Caughey B |date=August 1994 |title=Cell-free formation of protease-resistant prion protein |journal=Nature |volume=370 |issue=6489 |pages=471–4 |bibcode=1994Natur.370..471K |doi=10.1038/370471a0 |pmid=7913989 |s2cid=4337709 |hdl-access=free |hdl=1721.1/42578}}</ref> and Soto ''et al''. demonstrated sustained amplification of PrP<sup>res</sup> and prion infectivity by a procedure involving [[Protein misfolding cyclic amplification|cyclic amplification of protein misfolding]].<ref name="pmid11459061">{{cite journal |vauthors=Saborio GP, Permanne B, Soto C |date=June 2001 |title=Sensitive detection of pathological prion protein by cyclic amplification of protein misfolding |journal=Nature |volume=411 |issue=6839 |pages=810–3 |bibcode=2001Natur.411..810S |doi=10.1038/35081095 |pmid=11459061 |s2cid=4317585}}</ref> The term "PrP<sup>res</sup>" may refer either to protease-resistant forms of PrP<sup>Sc</sup>, which is isolated from infectious tissue and associated with the transmissible spongiform encephalopathy agent, or to other protease-resistant forms of PrP that, for example, might be generated ''in vitro''.<ref name="pmid15297610">{{cite journal |vauthors=Bieschke J, Weber P, Sarafoff N, Beekes M, Giese A, Kretzschmar H |date=August 2004 |title=Autocatalytic self-propagation of misfolded prion protein |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=101 |issue=33 |pages=12207–11 |bibcode=2004PNAS..10112207B |doi=10.1073/pnas.0404650101 |pmc=514458 |pmid=15297610 |doi-access=free}}</ref> Accordingly, unlike PrP<sup>Sc</sup>, PrP<sup>res</sup> may not necessarily be infectious.
+Protease-resistant PrP<sup>Sc</sup>-like protein (PrP<sup>res</sup>) is the name given to any isoform of PrP<sup>c</sup> which is structurally altered and converted into a misfolded [[proteinase K]]-resistant form.<ref>{{cite journal | vauthors = Riesner D | title = Biochemistry and structure of PrP(C) and PrP(Sc) | journal = British Medical Bulletin | volume = 66 | issue = 1 | pages = 21–33 | date = June 2003 | pmid = 14522846 | doi = 10.1093/bmb/66.1.21 | doi-access = free }}</ref> To model conversion of PrP<sup>C</sup> to PrP<sup>Sc</sup> ''in vitro'', Kocisko ''et al''. showed that PrP<sup>Sc</sup> could cause PrP<sup>C</sup> to convert to PrP<sup>res</sup> under cell-free conditions <ref name="pmid7913989">{{cite journal | vauthors = Kocisko DA, Come JH, Priola SA, Chesebro B, Raymond GJ, Lansbury PT, Caughey B | title = Cell-free formation of protease-resistant prion protein | journal = Nature | volume = 370 | issue = 6489 | pages = 471–474 | date = August 1994 | pmid = 7913989 | doi = 10.1038/370471a0 | bibcode = 1994Natur.370..471K | hdl-access = free | s2cid = 4337709 | hdl = 1721.1/42578 }}</ref> and Soto ''et al''. demonstrated sustained amplification of PrP<sup>res</sup> and prion infectivity by a procedure involving [[Protein misfolding cyclic amplification|cyclic amplification of protein misfolding]].<ref name="pmid11459061">{{cite journal | vauthors = Saborio GP, Permanne B, Soto C | title = Sensitive detection of pathological prion protein by cyclic amplification of protein misfolding | journal = Nature | volume = 411 | issue = 6839 | pages = 810–813 | date = June 2001 | pmid = 11459061 | doi = 10.1038/35081095 | bibcode = 2001Natur.411..810S | s2cid = 4317585 }}</ref> The term "PrP<sup>res</sup>" may refer either to protease-resistant forms of PrP<sup>Sc</sup>, which is isolated from infectious tissue and associated with the transmissible spongiform encephalopathy agent, or to other protease-resistant forms of PrP that, for example, might be generated ''in vitro''.<ref name="pmid15297610">{{cite journal | vauthors = Bieschke J, Weber P, Sarafoff N, Beekes M, Giese A, Kretzschmar H | title = Autocatalytic self-propagation of misfolded prion protein | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 33 | pages = 12207–12211 | date = August 2004 | pmid = 15297610 | pmc = 514458 | doi = 10.1073/pnas.0404650101 | bibcode = 2004PNAS..10112207B | doi-access = free }}</ref> Accordingly, unlike PrP<sup>Sc</sup>, PrP<sup>res</sup> may not necessarily be infectious.
 [[File:Prion structure membrane bound fibril.jpg|thumb|Models of normal (PrP<sup>C</sup>) and infectious (PrP<sup>Sc</sup>) forms of prion protein on a membrane: polypeptide (turquoise); glycans (red); glycolipid anchors (blue). The core structures are based on NMR spectroscopy (PrP<sup>C</sup>) and cryo-electron microscopy (PrP<sup>Sc</sup>).]]
@@ Line 54: / Line 54: @@
 ==== PrP and regulated cell death ====
-MAVS, RIP1, and RIP3 are prion-like proteins found in other parts of the body. They also polymerise into filamentous amyloid fibers which initiate regulated cell death in the case of a viral infection to prevent the spread of [[Virus#Etymology|virions]] to other, surrounding cells.<ref>{{cite journal | title = Necroptosis in anti-viral inflammation | journal = Nature | vauthors =Nailwal H, Chan FK | volume = 26 | issue = 1 | pages = 4–13 | doi = 10.1038/s41418-018-0172-x| pmid = 30050058 | pmc = 6294789 | year = 2019 }}</ref>
+MAVS, RIP1, and RIP3 are prion-like proteins found in other parts of the body. They also polymerise into filamentous amyloid fibers which initiate regulated cell death in the case of a viral infection to prevent the spread of [[Virus#Etymology|virions]] to other, surrounding cells.<ref>{{cite journal | vauthors = Nailwal H, Chan FK | title = Necroptosis in anti-viral inflammation | journal = Cell Death and Differentiation | volume = 26 | issue = 1 | pages = 4–13 | date = January 2019 | pmid = 30050058 | pmc = 6294789 | doi = 10.1038/s41418-018-0172-x }}</ref>
 ==== PrP and long-term memory ====
-A review of evidence in 2005 suggested that PrP may have a normal function in maintenance of [[long-term memory]].<ref>{{cite journal | vauthors = Shorter J, Lindquist S | s2cid = 5575951 | title = Prions as adaptive conduits of memory and inheritance | journal = Nature Reviews Genetics | volume = 6 | issue = 6 | pages = 435–50 | date = June 2005 | pmid = 15931169 | doi = 10.1038/nrg1616 }}</ref> As well, a 2004 study found that mice lacking genes for normal cellular PrP protein show altered [[hippocampus|hippocampal]] [[long-term potentiation]].<ref>{{cite journal | vauthors = Maglio LE, Perez MF, Martins VR, Brentani RR, Ramirez OA | title = Hippocampal synaptic plasticity in mice devoid of cellular prion protein | journal = Brain Research. Molecular Brain Research | volume = 131 | issue = 1–2 | pages = 58–64 | date = November 2004 | pmid = 15530652 | doi = 10.1016/j.molbrainres.2004.08.004 }}</ref><ref>{{cite journal | vauthors = Caiati MD, Safiulina VF, Fattorini G, Sivakumaran S, Legname G, Cherubini E | title = PrPC controls via protein kinase A the direction of synaptic plasticity in the immature hippocampus | journal = The Journal of Neuroscience | volume = 33 | issue = 7 | pages = 2973–83 | date = February 2013 | pmid = 23407955 | pmc = 6619229 | doi = 10.1523/JNEUROSCI.4149-12.2013 }}</ref> A recent study that also suggests why this might be the case, found that neuronal protein [[CPEB]] has a similar genetic sequence to yeast prion proteins. The prion-like formation of CPEB is essential for maintaining long-term synaptic changes associated with long-term memory formation.<ref>{{cite journal | vauthors = Sudhakarana IP, Ramaswamia M | title = Long-term memory consolidation: The role of RNA-binding proteins with prion-like domains | journal = RNA Biology | volume = 14 | issue = 5 | pages = 568–86 | date = 2016-10-11 | pmc = 5449092 | pmid = 27726526 | doi = 10.1080/15476286.2016.1244588 }}</ref>
+A review of evidence in 2005 suggested that PrP may have a normal function in maintenance of [[long-term memory]].<ref>{{cite journal | vauthors = Shorter J, Lindquist S | title = Prions as adaptive conduits of memory and inheritance | journal = Nature Reviews. Genetics | volume = 6 | issue = 6 | pages = 435–450 | date = June 2005 | pmid = 15931169 | doi = 10.1038/nrg1616 | s2cid = 5575951 }}</ref> As well, a 2004 study found that mice lacking genes for normal cellular PrP protein show altered [[hippocampus|hippocampal]] [[long-term potentiation]].<ref>{{cite journal | vauthors = Maglio LE, Perez MF, Martins VR, Brentani RR, Ramirez OA | title = Hippocampal synaptic plasticity in mice devoid of cellular prion protein | journal = Brain Research. Molecular Brain Research | volume = 131 | issue = 1-2 | pages = 58–64 | date = November 2004 | pmid = 15530652 | doi = 10.1016/j.molbrainres.2004.08.004 }}</ref><ref>{{cite journal | vauthors = Caiati MD, Safiulina VF, Fattorini G, Sivakumaran S, Legname G, Cherubini E | title = PrPC controls via protein kinase A the direction of synaptic plasticity in the immature hippocampus | journal = The Journal of Neuroscience | volume = 33 | issue = 7 | pages = 2973–2983 | date = February 2013 | pmid = 23407955 | pmc = 6619229 | doi = 10.1523/JNEUROSCI.4149-12.2013 }}</ref> A recent study that also suggests why this might be the case, found that neuronal protein [[CPEB]] has a similar genetic sequence to yeast prion proteins. The prion-like formation of CPEB is essential for maintaining long-term synaptic changes associated with long-term memory formation.<ref>{{cite journal | vauthors = Sudhakaran IP, Ramaswami M | title = Long-term memory consolidation: The role of RNA-binding proteins with prion-like domains | journal = RNA Biology | volume = 14 | issue = 5 | pages = 568–586 | date = May 2017 | pmid = 27726526 | pmc = 5449092 | doi = 10.1080/15476286.2016.1244588 }}</ref>
 ==== PrP and stem cell renewal ====
-A 2006 article from the Whitehead Institute for Biomedical Research indicates that PrP expression on stem cells is necessary for an organism's self-renewal of [[bone marrow]]. The study showed that all long-term [[hematopoietic stem cell]]s express PrP on their cell membrane and that hematopoietic tissues with PrP-null stem cells exhibit increased sensitivity to cell depletion.<ref>{{cite journal | vauthors = Zhang CC, Steele AD, Lindquist S, Lodish HF | title = Prion protein is expressed on long-term repopulating hematopoietic stem cells and is important for their self-renewal | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 7 | pages = 2184–89 | date = February 2006 | pmid = 16467153 | pmc = 1413720 | doi = 10.1073/pnas.0510577103 | bibcode = 2006PNAS..103.2184Z | doi-access = free }}</ref>
+A 2006 article from the Whitehead Institute for Biomedical Research indicates that PrP expression on stem cells is necessary for an organism's self-renewal of [[bone marrow]]. The study showed that all long-term [[hematopoietic stem cell]]s express PrP on their cell membrane and that hematopoietic tissues with PrP-null stem cells exhibit increased sensitivity to cell depletion.<ref>{{cite journal | vauthors = Zhang CC, Steele AD, Lindquist S, Lodish HF | title = Prion protein is expressed on long-term repopulating hematopoietic stem cells and is important for their self-renewal | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 7 | pages = 2184–2189 | date = February 2006 | pmid = 16467153 | pmc = 1413720 | doi = 10.1073/pnas.0510577103 | doi-access = free | bibcode = 2006PNAS..103.2184Z }}</ref>
 ==== PrP and innate immunity ====
-There is some evidence that PrP may play a role in [[innate immunity]], as the expression of [[PRNP]], the PrP gene, is upregulated in many viral infections and PrP has antiviral properties against many viruses, including [[HIV]].<ref>{{cite journal | vauthors = Lathe R, Darlix JL | title = Prion Protein PRNP: A New Player in Innate Immunity? The Aβ Connection | journal = Journal of Alzheimer's Disease Reports| volume = 1 | issue = 1 | pages = 263–275 | date = December 2017 | pmid = 30480243 | pmc = 6159716 | doi = 10.3233/ADR-170037 }}</ref>
+There is some evidence that PrP may play a role in [[innate immunity]], as the expression of [[PRNP]], the PrP gene, is upregulated in many viral infections and PrP has antiviral properties against many viruses, including [[HIV]].<ref>{{cite journal | vauthors = Lathe R, Darlix JL | title = Prion Protein PRNP: A New Player in Innate Immunity? The Aβ Connection | journal = Journal of Alzheimer's Disease Reports | volume = 1 | issue = 1 | pages = 263–275 | date = December 2017 | pmid = 30480243 | pmc = 6159716 | doi = 10.3233/ADR-170037 }}</ref>
 == Replication ==
@@ Line 69: / Line 69: @@
 [[File:Prion Replication.png|thumb|right|Fibril model of prion propagation.]]
-The first hypothesis that tried to explain how prions replicate in a protein-only manner was the [[Protein dimer|heterodimer]] model.<ref>{{cite journal | vauthors = Cohen FE, Pan KM, Huang Z, Baldwin M, Fletterick RJ, Prusiner SB | title = Structural clues to prion replication | journal = Science | volume = 264 | issue = 5158 | pages = 530–31 | date = April 1994 | pmid = 7909169 | doi = 10.1126/science.7909169 | bibcode = 1994Sci...264..530C }}</ref> This model assumed that a single PrP<sup>Sc</sup> molecule binds to a single PrP<sup>C</sup> molecule and [[enzyme|catalyzes]] its conversion into PrP<sup>Sc</sup>. The two PrP<sup>Sc</sup> molecules then come apart and can go on to convert more PrP<sup>C</sup>. However, a model of prion replication must explain both how prions propagate, and why their spontaneous appearance is so rare. [[Manfred Eigen]] showed that the heterodimer model requires PrP<sup>Sc</sup> to be an extraordinarily effective catalyst, increasing the rate of the conversion reaction by a factor of around 10<sup>15</sup>.<ref name="Eigen96">{{cite journal | vauthors = Eigen M | title = Prionics or the kinetic basis of prion diseases | journal = Biophysical Chemistry | volume = 63 | issue = 1 | pages = A1–18 | date = December 1996 | pmid = 8981746 | doi = 10.1016/S0301-4622(96)02250-8 }}</ref> This problem does not arise if PrP<sup>Sc</sup> exists only in aggregated forms such as [[amyloid]], where [[cooperativity]] may act as a barrier to spontaneous conversion. What is more, despite considerable effort, infectious monomeric PrP<sup>Sc</sup> has never been isolated.<ref>{{Cite journal |last1=Vázquez-Fernández |first1=E. |last2=Young |first2=H. S. |last3=Requena |first3=J. R. |last4=Wille |first4=H. |date=2017 |title=The Structure of Mammalian Prions and Their Aggregates |url=https://www.sciencedirect.com/science/article/abs/pii/S193764481630082X |journal=International Review of Cell and Molecular Biology |volume=329 |pages=277–301 |doi=10.1016/bs.ircmb.2016.08.013 |issn=1937-6448 |pmid=28109330|isbn=978-0-12-812251-8 }}</ref>
+The first hypothesis that tried to explain how prions replicate in a protein-only manner was the [[Protein dimer|heterodimer]] model.<ref>{{cite journal | vauthors = Cohen FE, Pan KM, Huang Z, Baldwin M, Fletterick RJ, Prusiner SB | title = Structural clues to prion replication | journal = Science | volume = 264 | issue = 5158 | pages = 530–531 | date = April 1994 | pmid = 7909169 | doi = 10.1126/science.7909169 | bibcode = 1994Sci...264..530C }}</ref> This model assumed that a single PrP<sup>Sc</sup> molecule binds to a single PrP<sup>C</sup> molecule and [[enzyme|catalyzes]] its conversion into PrP<sup>Sc</sup>. The two PrP<sup>Sc</sup> molecules then come apart and can go on to convert more PrP<sup>C</sup>. However, a model of prion replication must explain both how prions propagate, and why their spontaneous appearance is so rare. [[Manfred Eigen]] showed that the heterodimer model requires PrP<sup>Sc</sup> to be an extraordinarily effective catalyst, increasing the rate of the conversion reaction by a factor of around 10<sup>15</sup>.<ref name="Eigen96">{{cite journal | vauthors = Eigen M | title = Prionics or the kinetic basis of prion diseases | journal = Biophysical Chemistry | volume = 63 | issue = 1 | pages = A1-18 | date = December 1996 | pmid = 8981746 | doi = 10.1016/S0301-4622(96)02250-8 }}</ref> This problem does not arise if PrP<sup>Sc</sup> exists only in aggregated forms such as [[amyloid]], where [[cooperativity]] may act as a barrier to spontaneous conversion. What is more, despite considerable effort, infectious monomeric PrP<sup>Sc</sup> has never been isolated.<ref>{{cite journal | vauthors = Vázquez-Fernández E, Young HS, Requena JR, Wille H | title = The Structure of Mammalian Prions and Their Aggregates | journal = International Review of Cell and Molecular Biology | volume = 329 | pages = 277–301 | date = 2017 | pmid = 28109330 | doi = 10.1016/bs.ircmb.2016.08.013 | isbn = 978-0-12-812251-8 }}</ref>
-An alternative model assumes that PrP<sup>Sc</sup> exists only as [[fibril]]s, and that fibril ends bind PrP<sup>C</sup> and convert it into PrP<sup>Sc</sup>. If this were all, then the quantity of prions would increase [[linear function|linearly]], forming ever longer fibrils. But [[exponential growth]] of both PrP<sup>Sc</sup> and of the [[Median lethal dose|quantity of infectious particles]] is observed during prion disease.<ref>{{cite journal | vauthors = Bolton DC, Rudelli RD, Currie JR, Bendheim PE | title = Copurification of Sp33-37 and scrapie agent from hamster brain prior to detectable histopathology and clinical disease | journal = The Journal of General Virology | volume = 72 | issue = 12 | pages = 2905–13 | date = December 1991 | pmid = 1684986 | doi = 10.1099/0022-1317-72-12-2905 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Jendroska K, Heinzel FP, Torchia M, Stowring L, Kretzschmar HA, Kon A, Stern A, Prusiner SB, DeArmond SJ | s2cid = 13098083 | title = Proteinase-resistant prion protein accumulation in Syrian hamster brain correlates with regional pathology and scrapie infectivity | journal = Neurology | volume = 41 | issue = 9 | pages = 1482–90 | date = September 1991 | pmid = 1679911 | doi = 10.1212/WNL.41.9.1482 }}</ref><ref>{{cite journal | vauthors = Beekes M, Baldauf E, Diringer H | title = Sequential appearance and accumulation of pathognomonic markers in the central nervous system of hamsters orally infected with scrapie | journal = The Journal of General Virology | volume = 77 | issue = 8 | pages = 1925–34 | date = August 1996 | pmid = 8760444 | doi = 10.1099/0022-1317-77-8-1925 | doi-access = free }}</ref> This can be explained by taking into account fibril breakage.<ref>{{cite journal | vauthors = Bamborough P, Wille H, Telling GC, Yehiely F, Prusiner SB, Cohen FE | title = Prion protein structure and scrapie replication: theoretical, spectroscopic, and genetic investigations | journal = Cold Spring Harbor Symposia on Quantitative Biology | volume = 61 | pages = 495–509 | year = 1996 | pmid = 9246476 | doi = 10.1101/SQB.1996.061.01.050 | doi-broken-date = July 10, 2024 }}</ref> A mathematical solution for the exponential growth rate resulting from the combination of fibril growth and fibril breakage has been found.<ref name="Masel 99" /> The exponential growth rate depends largely on the [[square root]] of the PrP<sup>C</sup> concentration.<ref name="Masel 99" /> The [[incubation period]] is determined by the exponential growth rate, and [[in vivo]] data on prion diseases in [[transgenic mice]] match this prediction.<ref name="Masel 99" /> The same square root dependence is also seen [[in vitro]] in experiments with a variety of different [[amyloid|amyloid proteins]].<ref>{{cite journal | vauthors = Knowles TP, Waudby CA, Devlin GL, Cohen SI, Aguzzi A, Vendruscolo M, Terentjev EM, Welland ME, Dobson CM | s2cid = 6267152 | title = An analytical solution to the kinetics of breakable filament assembly | journal = Science | volume = 326 | issue = 5959 | pages = 1533–37 | date = December 2009 | pmid = 20007899 | doi = 10.1126/science.1178250 | bibcode = 2009Sci...326.1533K }}</ref>
+An alternative model assumes that PrP<sup>Sc</sup> exists only as [[fibril]]s, and that fibril ends bind PrP<sup>C</sup> and convert it into PrP<sup>Sc</sup>. If this were all, then the quantity of prions would increase [[linear function|linearly]], forming ever longer fibrils. But [[exponential growth]] of both PrP<sup>Sc</sup> and of the [[Median lethal dose|quantity of infectious particles]] is observed during prion disease.<ref>{{cite journal | vauthors = Bolton DC, Rudelli RD, Currie JR, Bendheim PE | title = Copurification of Sp33-37 and scrapie agent from hamster brain prior to detectable histopathology and clinical disease | journal = The Journal of General Virology | volume = 72 | issue = 12 | pages = 2905–2913 | date = December 1991 | pmid = 1684986 | doi = 10.1099/0022-1317-72-12-2905 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Jendroska K, Heinzel FP, Torchia M, Stowring L, Kretzschmar HA, Kon A, Stern A, Prusiner SB, DeArmond SJ | title = Proteinase-resistant prion protein accumulation in Syrian hamster brain correlates with regional pathology and scrapie infectivity | journal = Neurology | volume = 41 | issue = 9 | pages = 1482–1490 | date = September 1991 | pmid = 1679911 | doi = 10.1212/WNL.41.9.1482 | s2cid = 13098083 }}</ref><ref>{{cite journal | vauthors = Beekes M, Baldauf E, Diringer H | title = Sequential appearance and accumulation of pathognomonic markers in the central nervous system of hamsters orally infected with scrapie | journal = The Journal of General Virology | volume = 77 ( Pt 8) | issue = 8 | pages = 1925–1934 | date = August 1996 | pmid = 8760444 | doi = 10.1099/0022-1317-77-8-1925 | doi-access = free }}</ref> This can be explained by taking into account fibril breakage.<ref>{{cite journal | vauthors = Bamborough P, Wille H, Telling GC, Yehiely F, Prusiner SB, Cohen FE | title = Prion protein structure and scrapie replication: theoretical, spectroscopic, and genetic investigations | journal = Cold Spring Harbor Symposia on Quantitative Biology | volume = 61 | pages = 495–509 | year = 1996 | pmid = 9246476 | doi = 10.1101/SQB.1996.061.01.050 | doi-broken-date = July 10, 2024 }}</ref> A mathematical solution for the exponential growth rate resulting from the combination of fibril growth and fibril breakage has been found.<ref name="Masel 99" /> The exponential growth rate depends largely on the [[square root]] of the PrP<sup>C</sup> concentration.<ref name="Masel 99" /> The [[incubation period]] is determined by the exponential growth rate, and [[in vivo]] data on prion diseases in [[transgenic mice]] match this prediction.<ref name="Masel 99" /> The same square root dependence is also seen [[in vitro]] in experiments with a variety of different [[amyloid|amyloid proteins]].<ref>{{cite journal | vauthors = Knowles TP, Waudby CA, Devlin GL, Cohen SI, Aguzzi A, Vendruscolo M, Terentjev EM, Welland ME, Dobson CM | title = An analytical solution to the kinetics of breakable filament assembly | journal = Science | volume = 326 | issue = 5959 | pages = 1533–1537 | date = December 2009 | pmid = 20007899 | doi = 10.1126/science.1178250 | s2cid = 6267152 | bibcode = 2009Sci...326.1533K }}</ref>
-The mechanism of prion replication has implications for designing drugs. Since the incubation period of prion diseases is so long, an effective drug does not need to eliminate all prions, but simply needs to slow down the rate of exponential growth. Models predict that the most effective way to achieve this, using a drug with the lowest possible dose, is to find a drug that binds to fibril ends and blocks them from growing any further.<ref>{{cite journal | vauthors = Masel J, Jansen VA | title = Designing drugs to stop the formation of prion aggregates and other amyloids | journal = Biophysical Chemistry | volume = 88 | issue = 1–3 | pages = 47–59 | date = December 2000 | pmid = 11152275 | doi = 10.1016/S0301-4622(00)00197-6 }}</ref>
+The mechanism of prion replication has implications for designing drugs. Since the incubation period of prion diseases is so long, an effective drug does not need to eliminate all prions, but simply needs to slow down the rate of exponential growth. Models predict that the most effective way to achieve this, using a drug with the lowest possible dose, is to find a drug that binds to fibril ends and blocks them from growing any further.<ref>{{cite journal | vauthors = Masel J, Jansen VA | title = Designing drugs to stop the formation of prion aggregates and other amyloids | journal = Biophysical Chemistry | volume = 88 | issue = 1-3 | pages = 47–59 | date = December 2000 | pmid = 11152275 | doi = 10.1016/S0301-4622(00)00197-6 }}</ref>
-Researchers at Dartmouth College discovered that endogenous host cofactor molecules such as the phospholipid molecule (e.g. phosphatidylethanolamine) and [[polyanions]] (e.g. single stranded RNA molecules) are necessary to form PrP<sup>Sc</sup> molecules with high levels of specific infectivity ''in vitro'', whereas protein-only PrP<sup>Sc</sup> molecules appear to lack significant levels of biological infectivity.<ref name="Formation of native prions from min">{{cite journal | vauthors = Deleault NR, Harris BT, Rees JR, Supattapone S | title = Formation of native prions from minimal components in vitro | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 104 | issue = 23 | pages = 9741–6 | date = June 2007 | pmid = 17535913 | pmc = 1887554 | doi = 10.1073/pnas.0702662104 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Deleault NR, Walsh DJ, Piro JR, Wang F, Wang X, Ma J, Rees JR, Supattapone S | display-authors = 6 | title = Cofactor molecules maintain infectious conformation and restrict strain properties in purified prions | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 109 | issue = 28 | pages = E1938-46 | date = July 2012 | pmid = 22711839 | pmc = 3396481 | doi = 10.1073/pnas.1206999109 | doi-access = free }}</ref>
+Researchers at Dartmouth College discovered that endogenous host cofactor molecules such as the phospholipid molecule (e.g. phosphatidylethanolamine) and [[polyanions]] (e.g. single stranded RNA molecules) are necessary to form PrP<sup>Sc</sup> molecules with high levels of specific infectivity ''in vitro'', whereas protein-only PrP<sup>Sc</sup> molecules appear to lack significant levels of biological infectivity.<ref name="Formation of native prions from min">{{cite journal | vauthors = Deleault NR, Harris BT, Rees JR, Supattapone S | title = Formation of native prions from minimal components in vitro | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 104 | issue = 23 | pages = 9741–9746 | date = June 2007 | pmid = 17535913 | pmc = 1887554 | doi = 10.1073/pnas.0702662104 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Deleault NR, Walsh DJ, Piro JR, Wang F, Wang X, Ma J, Rees JR, Supattapone S | title = Cofactor molecules maintain infectious conformation and restrict strain properties in purified prions | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 109 | issue = 28 | pages = E1938-E1946 | date = July 2012 | pmid = 22711839 | pmc = 3396481 | doi = 10.1073/pnas.1206999109 | doi-access = free }}</ref>
 == Transmissible spongiform encephalopathies ==
@@ Line 91: / Line 91: @@
 |[[Bovine spongiform encephalopathy]]<ref name="ictvdb-prions" />
 |-
-|[[Camel]]<ref>{{cite journal | vauthors = Babelhadj B, Di Bari MA, Pirisinu L, Chiappini B, Gaouar SB, Riccardi G, Marcon S, Agrimi U, Nonno R, Vaccari G | title = Prion Disease in Dromedary Camels, Algeria | journal = Emerging Infectious Diseases | volume = 24 | issue = 6 | pages = 1029–36 | date = June 2018 | pmid = 29652245 | pmc = 6004840 | doi = 10.3201/eid2406.172007 }}</ref>
+|[[Camel]]<ref>{{cite journal | vauthors = Babelhadj B, Di Bari MA, Pirisinu L, Chiappini B, Gaouar SB, Riccardi G, Marcon S, Agrimi U, Nonno R, Vaccari G | title = Prion Disease in Dromedary Camels, Algeria | journal = Emerging Infectious Diseases | volume = 24 | issue = 6 | pages = 1029–1036 | date = June 2018 | pmid = 29652245 | pmc = 6004840 | doi = 10.3201/eid2406.172007 }}</ref>
 |[[Camel spongiform encephalopathy]] (CSE)
 |-
@@ Line 122: / Line 122: @@
 |[[Gerstmann–Sträussler–Scheinker syndrome]] (GSS)<ref name="ictvdb-prions" />
 |-
-|[[Fatal insomnia]] (FFI)<ref>{{cite journal |vauthors=Mastrianni JA, Nixon R, Layzer R, Telling GC, Han D, DeArmond SJ, Prusiner SB |title=Prion protein conformation in a patient with sporadic fatal insomnia |journal=The New England Journal of Medicine |volume=340 |issue=21 |pages=1630–1638 |date=May 1999 |pmid=10341275 |doi=10.1056/NEJM199905273402104|doi-access=free }}<br />Lay summary: {{cite web |title=BSE proteins may cause fatal insomnia |url=http://news.bbc.co.uk/2/hi/health/355297.stm |date=May 28, 1999|website=BBC News}}</ref>
+|[[Fatal insomnia]] (FFI)<ref>{{cite journal | vauthors = Mastrianni JA, Nixon R, Layzer R, Telling GC, Han D, DeArmond SJ, Prusiner SB | title = Prion protein conformation in a patient with sporadic fatal insomnia | journal = The New England Journal of Medicine | volume = 340 | issue = 21 | pages = 1630–1638 | date = May 1999 | pmid = 10341275 | doi = 10.1056/NEJM199905273402104 | doi-access = free }}<br />Lay summary: {{cite web |title=BSE proteins may cause fatal insomnia |url=http://news.bbc.co.uk/2/hi/health/355297.stm |date=May 28, 1999|website=BBC News}}</ref>
 |-
 |[[Kuru (disease)|Kuru]]<ref name="ictvdb-prions" />
 |-
-| <!---Familiar spongiform encephalopathy associated with a novel prion protein gene mutation--->Familial spongiform encephalopathy<ref>{{cite journal | vauthors = Nitrini R, Rosemberg S, Passos-Bueno MR, da Silva LS, Iughetti P, Papadopoulos M, Carrilho PM, Caramelli P, Albrecht S, Zatz M, LeBlanc A | title = Familial spongiform encephalopathy associated with a novel prion protein gene mutation | journal = Annals of Neurology | volume = 42 | issue = 2 | pages = 138–46 | date = August 1997 | pmid = 9266722 | doi = 10.1002/ana.410420203 | s2cid = 22600579 }}</ref>
+| <!---Familiar spongiform encephalopathy associated with a novel prion protein gene mutation--->Familial spongiform encephalopathy<ref>{{cite journal | vauthors = Nitrini R, Rosemberg S, Passos-Bueno MR, da Silva LS, Iughetti P, Papadopoulos M, Carrilho PM, Caramelli P, Albrecht S, Zatz M, LeBlanc A | title = Familial spongiform encephalopathy associated with a novel prion protein gene mutation | journal = Annals of Neurology | volume = 42 | issue = 2 | pages = 138–146 | date = August 1997 | pmid = 9266722 | doi = 10.1002/ana.410420203 | s2cid = 22600579 }}</ref>
 |-
 |[[Variably protease-sensitive prionopathy]] (VPSPr)
@@ Line 132: / Line 132: @@
 |}
-Prions cause neurodegenerative disease by aggregating extracellularly within the [[central nervous system]] to form plaques known as [[amyloids]], which disrupt the normal [[tissue (biology)|tissue]] structure. This disruption is characterized by "holes" in the tissue with resultant spongy architecture due to the [[vacuole]] formation in the neurons.<ref name="robspath">{{cite book | veditors = Robbins SL, Cotran RS, Kumar V, Collins T | title = Robbins pathologic basis of disease | publisher = Saunders | location = Philadelphia | year =1999 | isbn = 072167335X }}</ref> Other histological changes include [[astrogliosis]] and the absence of an [[inflammation|inflammatory reaction]].<ref name="belay">{{cite journal | vauthors = Belay ED | title = Transmissible spongiform encephalopathies in humans | journal = Annual Review of Microbiology | volume = 53 | pages = 283–314 | year = 1999 | pmid = 10547693 | doi = 10.1146/annurev.micro.53.1.283 | s2cid = 18648029 | url = https://zenodo.org/record/1235027 }}</ref> While the [[incubation period]] for prion diseases is relatively long (5 to 20 years), once symptoms appear the disease progresses rapidly, leading to brain damage and death.<ref name="cdc">{{cite web|url=https://www.cdc.gov/ncidod/dvrd/prions/|title=Prion Diseases|date=2006-01-26|access-date=2010-02-28|publisher=US Centers for Disease Control|archive-url=https://web.archive.org/web/20100304135757/http://www.cdc.gov/ncidod/dvrd/prions/|archive-date=2010-03-04|url-status=dead}}</ref> Neurodegenerative symptoms can include [[convulsion]]s, [[dementia]], [[ataxia]] (balance and coordination dysfunction), and behavioural or personality changes.<ref>{{Cite journal |last1=Imran |first1=Muhammad |last2=Mahmood |first2=Saqib |date=2011-12-24 |title=An overview of human prion diseases |journal=Virology Journal |volume=8 |issue=1 |pages=559 |doi=10.1186/1743-422X-8-559 |doi-access=free |issn=1743-422X |pmc=3296552 |pmid=22196171}}</ref><ref>{{Cite journal |last=Mastrianni |first=James A. |date=2010-04-01 |title=The genetics of prion diseases |journal=Genetics in Medicine |volume=12 |issue=4 |pages=187–195 |doi=10.1097/GIM.0b013e3181cd7374 |issn=1098-3600 |pmid=20216075|doi-access=free }}</ref>
+Prions cause neurodegenerative disease by aggregating extracellularly within the [[central nervous system]] to form plaques known as [[amyloids]], which disrupt the normal [[tissue (biology)|tissue]] structure. This disruption is characterized by "holes" in the tissue with resultant spongy architecture due to the [[vacuole]] formation in the neurons.<ref name="robspath">{{cite book | veditors = Robbins SL, Cotran RS, Kumar V, Collins T | title = Robbins pathologic basis of disease | publisher = Saunders | location = Philadelphia | year =1999 | isbn = 072167335X }}</ref> Other histological changes include [[astrogliosis]] and the absence of an [[inflammation|inflammatory reaction]].<ref name="belay">{{cite journal | vauthors = Belay ED | title = Transmissible spongiform encephalopathies in humans | journal = Annual Review of Microbiology | volume = 53 | pages = 283–314 | year = 1999 | pmid = 10547693 | doi = 10.1146/annurev.micro.53.1.283 | s2cid = 18648029 }}</ref> While the [[incubation period]] for prion diseases is relatively long (5 to 20 years), once symptoms appear the disease progresses rapidly, leading to brain damage and death.<ref name="cdc">{{cite web|url=https://www.cdc.gov/ncidod/dvrd/prions/|title=Prion Diseases|date=2006-01-26|access-date=2010-02-28|publisher=US Centers for Disease Control|archive-url=https://web.archive.org/web/20100304135757/http://www.cdc.gov/ncidod/dvrd/prions/|archive-date=2010-03-04|url-status=dead}}</ref> Neurodegenerative symptoms can include [[convulsion]]s, [[dementia]], [[ataxia]] (balance and coordination dysfunction), and behavioural or personality changes.<ref>{{cite journal | vauthors = Imran M, Mahmood S | title = An overview of human prion diseases | journal = Virology Journal | volume = 8 | issue = 1 | pages = 559 | date = December 2011 | pmid = 22196171 | pmc = 3296552 | doi = 10.1186/1743-422X-8-559 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Mastrianni JA | title = The genetics of prion diseases | journal = Genetics in Medicine | volume = 12 | issue = 4 | pages = 187–195 | date = April 2010 | pmid = 20216075 | doi = 10.1097/GIM.0b013e3181cd7374 | doi-access = free }}</ref>
-Many different mammalian species can be affected by prion diseases, as the prion protein (PrP) is very similar in all mammals.<ref>{{cite journal | vauthors = Collinge J | s2cid = 18915904 | title = Prion diseases of humans and animals: their causes and molecular basis | journal = Annual Review of Neuroscience | volume = 24 | pages = 519–50 | year = 2001 | pmid = 11283320 | doi = 10.1146/annurev.neuro.24.1.519 | url = http://pdfs.semanticscholar.org/650f/8f4c880880d357e5dd82236ba611065e21cc.pdf | archive-url = https://web.archive.org/web/20190225162649/http://pdfs.semanticscholar.org/650f/8f4c880880d357e5dd82236ba611065e21cc.pdf | url-status = dead | archive-date = 2019-02-25 }}</ref> Due to small differences in PrP between different species it is unusual for a prion disease to transmit from one species to another. The human prion disease variant Creutzfeldt–Jakob disease, however, is thought to be caused by a prion that typically infects cattle, causing [[bovine spongiform encephalopathy]] and is transmitted through infected meat.<ref name="ironside">{{cite journal | vauthors = Ironside JW | title = Variant Creutzfeldt–Jakob disease: risk of transmission by blood transfusion and blood therapies | journal = Haemophilia | volume = 12 | issue = Suppl 1 | pages = 8–15, discussion 26–28 | date = March 2006 | pmid = 16445812 | doi = 10.1111/j.1365-2516.2006.01195.x | doi-access = free }}</ref>
+Many different mammalian species can be affected by prion diseases, as the prion protein (PrP) is very similar in all mammals.<ref>{{cite journal | vauthors = Collinge J | title = Prion diseases of humans and animals: their causes and molecular basis | journal = Annual Review of Neuroscience | volume = 24 | pages = 519–550 | year = 2001 | pmid = 11283320 | doi = 10.1146/annurev.neuro.24.1.519 | url = http://pdfs.semanticscholar.org/650f/8f4c880880d357e5dd82236ba611065e21cc.pdf | url-status = dead | s2cid = 18915904 | archive-url = https://web.archive.org/web/20190225162649/http://pdfs.semanticscholar.org/650f/8f4c880880d357e5dd82236ba611065e21cc.pdf | archive-date = 2019-02-25 }}</ref> Due to small differences in PrP between different species it is unusual for a prion disease to transmit from one species to another. The human prion disease variant Creutzfeldt–Jakob disease, however, is thought to be caused by a prion that typically infects cattle, causing [[bovine spongiform encephalopathy]] and is transmitted through infected meat.<ref name="ironside">{{cite journal | vauthors = Ironside JW | title = Variant Creutzfeldt-Jakob disease: risk of transmission by blood transfusion and blood therapies | journal = Haemophilia | volume = 12 | issue = Suppl 1 | pages = 8–15, discussion 26–28 | date = March 2006 | pmid = 16445812 | doi = 10.1111/j.1365-2516.2006.01195.x | doi-access = free }}</ref>
-All known prion diseases are untreatable and fatal.<ref name=":0" /><ref name="gilch">{{cite journal |vauthors=Gilch S, Winklhofer KF, Groschup MH, Nunziante M, Lucassen R, Spielhaupter C, Muranyi W, Riesner D, Tatzelt J, Schätzl HM |title=Intracellular re-routing of prion protein prevents propagation of PrP(Sc) and delays onset of prion disease |journal=The EMBO Journal |volume=20 |issue=15 |pages=3957–3966 |date=August 2001 |pmid=11483499 |pmc=149175 |doi=10.1093/emboj/20.15.3957}}</ref><ref>{{Cite journal |last1=Agarwal |first1=Aishwarya |last2=Mukhopadhyay |first2=Samrat |date=2022-01-15 |title=Prion Protein Biology Through the Lens of Liquid-Liquid Phase Separation |url=https://pubmed.ncbi.nlm.nih.gov/34808226/ |journal=Journal of Molecular Biology |volume=434 |issue=1 |pages=167368 |doi=10.1016/j.jmb.2021.167368 |issn=1089-8638 |pmid=34808226}}</ref>
+All known prion diseases are untreatable and fatal.<ref name=":0" /><ref name="gilch">{{cite journal | vauthors = Gilch S, Winklhofer KF, Groschup MH, Nunziante M, Lucassen R, Spielhaupter C, Muranyi W, Riesner D, Tatzelt J, Schätzl HM | title = Intracellular re-routing of prion protein prevents propagation of PrP(Sc) and delays onset of prion disease | journal = The EMBO Journal | volume = 20 | issue = 15 | pages = 3957–3966 | date = August 2001 | pmid = 11483499 | pmc = 149175 | doi = 10.1093/emboj/20.15.3957 }}</ref><ref>{{cite journal | vauthors = Agarwal A, Mukhopadhyay S | title = Prion Protein Biology Through the Lens of Liquid-Liquid Phase Separation | journal = Journal of Molecular Biology | volume = 434 | issue = 1 | pages = 167368 | date = January 2022 | pmid = 34808226 | doi = 10.1016/j.jmb.2021.167368 }}</ref>
 Until 2015 all known mammalian prion diseases were considered to be caused by the prion protein, [[PRNP|PrP]]; in 2015 [[multiple system atrophy]] was found to be transmissible and was hypothesized to be caused by a new prion, the misfolded form of a protein called [[alpha-synuclein]].<ref name=pmid26324905/> The endogenous, properly folded form of the prion protein is denoted PrP<sup>C</sup> (for '''''C'''ommon'' or '''''C'''ellular''), whereas the disease-linked, misfolded form is denoted PrP<sup>Sc</sup> (for '''''Sc'''rapie''), after one of the diseases first linked to prions and neurodegeneration.<ref name=Krull /><ref name="pmid19242475"/> The precise structure of the prion is not known, though they can be formed spontaneously by combining PrP<sup>C</sup>, homopolymeric polyadenylic acid, and lipids in a [[protein misfolding cyclic amplification]] (PMCA) reaction even in the absence of pre-existing infectious prions.<ref name="Formation of native prions from min"/> This result is further evidence that prion replication does not require genetic information.<ref name="pmid28838669">{{cite journal | vauthors = Moda F | title = Protein Misfolding Cyclic Amplification of Infectious Prions | journal = Progress in Molecular Biology and Translational Science | volume = 150 | pages = 361–374 | date = 2017 | pmid = 28838669 | doi = 10.1016/bs.pmbts.2017.06.016 | isbn = 978-0-12-811226-7 }}</ref>
 === Transmission ===
-It has been recognized that prion diseases can arise in three different ways: acquired, familial, or sporadic.<ref>{{cite book | veditors = Groschup MH, Kretzschmar HA | title = Prion Diseases Diagnosis and Pathogeneis | series = Archives of Virology | volume = 16 | location = New York | publisher = Springer | year = 2001 | isbn=978-3-211-83530-2 }}</ref> It is often assumed that the diseased form directly interacts with the normal form to make it rearrange its structure. One idea, the "Protein X" hypothesis, is that an as-yet unidentified cellular protein (Protein X) enables the conversion of PrP<sup>C</sup> to PrP<sup>Sc</sup> by bringing a molecule of each of the two together into a complex.<ref>{{cite journal | vauthors = Telling GC, Scott M, Mastrianni J, Gabizon R, Torchia M, Cohen FE, DeArmond SJ, Prusiner SB | s2cid = 15235574 | title = Prion propagation in mice expressing human and chimeric PrP transgenes implicates the interaction of cellular PrP with another protein | journal = Cell | volume = 83 | issue = 1 | pages = 79–90 | date = October 1995 | pmid = 7553876 | doi = 10.1016/0092-8674(95)90236-8 | doi-access = free }}</ref>
+It has been recognized that prion diseases can arise in three different ways: acquired, familial, or sporadic.<ref>{{cite book | veditors = Groschup MH, Kretzschmar HA | title = Prion Diseases Diagnosis and Pathogeneis | series = Archives of Virology | volume = 16 | location = New York | publisher = Springer | year = 2001 | isbn=978-3-211-83530-2 }}</ref> It is often assumed that the diseased form directly interacts with the normal form to make it rearrange its structure. One idea, the "Protein X" hypothesis, is that an as-yet unidentified cellular protein (Protein X) enables the conversion of PrP<sup>C</sup> to PrP<sup>Sc</sup> by bringing a molecule of each of the two together into a complex.<ref>{{cite journal | vauthors = Telling GC, Scott M, Mastrianni J, Gabizon R, Torchia M, Cohen FE, DeArmond SJ, Prusiner SB | title = Prion propagation in mice expressing human and chimeric PrP transgenes implicates the interaction of cellular PrP with another protein | journal = Cell | volume = 83 | issue = 1 | pages = 79–90 | date = October 1995 | pmid = 7553876 | doi = 10.1016/0092-8674(95)90236-8 | s2cid = 15235574 | doi-access = free }}</ref>
-The primary method of infection in animals is through ingestion. It is thought that prions may be deposited in the environment through the remains of dead animals and via urine, saliva, and other body fluids. They may then linger in the soil by binding to clay and other minerals.<ref>{{cite journal | vauthors = Johnson CJ, Pedersen JA, Chappell RJ, McKenzie D, Aiken JM | title = Oral transmissibility of prion disease is enhanced by binding to soil particles | journal = PLOS Pathogens | volume = 3 | issue = 7 | pages = e93 | date = July 2007 | pmid = 17616973 | pmc = 1904474 | doi = 10.1371/journal.ppat.0030093 | doi-access = free }}</ref>
+The primary method of infection in animals is through ingestion. It is thought that prions may be deposited in the environment through the remains of dead animals and via urine, saliva, and other body fluids. They may then linger in the soil by binding to clay and other minerals.<ref>{{cite journal | vauthors = Johnson CJ, Pedersen JA, Chappell RJ, McKenzie D, Aiken JM | title = Oral transmissibility of prion disease is enhanced by binding to soil particles | journal = PLoS Pathogens | volume = 3 | issue = 7 | pages = e93 | date = July 2007 | pmid = 17616973 | pmc = 1904474 | doi = 10.1371/journal.ppat.0030093 | doi-access = free }}</ref>
-A [[University of California]] research team has provided evidence for the theory that infection can occur from prions in manure.<ref>{{cite journal |vauthors=Tamgüney G, Miller MW, Wolfe LL, Sirochman TM, Glidden DV, Palmer C, Lemus A, DeArmond SJ, Prusiner SB |title=Asymptomatic deer excrete infectious prions in faeces |journal=Nature |volume=461 |issue=7263 |pages=529–532 |date=September 2009 |pmid=19741608 |pmc=3186440 |doi=10.1038/nature08289 |bibcode=2009Natur.461..529T}}</ref> And, since manure is present in many areas surrounding water reservoirs, as well as used on many crop fields, it raises the possibility of widespread transmission. Although it was initially reported in January 2011 that researchers had discovered prions spreading through airborne transmission on [[aerosol]] particles in an [[animal testing]] experiment focusing on [[scrapie]] infection in [[laboratory mice]],<ref>{{cite journal |vauthors=Haybaeck J, Heikenwalder M, Klevenz B, Schwarz P, Margalith I, Bridel C, Mertz K, Zirdum E, Petsch B, Fuchs TJ, Stitz L, Aguzzi A |title=Aerosols transmit prions to immunocompetent and immunodeficient mice |journal=PLOS Pathogens |volume=7 |issue=1 |pages=e1001257 |date=January 2011 |pmid=21249178 |pmc=3020930 |doi=10.1371/journal.ppat.1001257 |doi-access=free }}{{Retracted|doi=10.1371/journal.ppat.1012396|pmid=39024193}}<br />Lay summary: {{cite web | vauthors = Mackenzie D |date=January 13, 2011 |title=Prion disease can spread through air |url=https://www.newscientist.com/article/dn19971-prion-disease-can-spread-through-air |url-access=registration |website=New Scientist}}</ref> this report was retracted in 2024.<ref>{{cite journal |vauthors=((The PLOS Pathogens Editors)), Haybaeck J, Heikenwalder M, Klevenz B, Schwarz P, Margalith I, Bridel C, Mertz K, Zirdum E, Petsch B, Fuchs TJ, Stitz L, Aguzzi A |title=Retraction: Aerosols transmit prions to immunocompetent and immunodeficient mice |journal=PLOS Pathogens |volume=20 |issue=7 |pages=e1012396 |date=July 2024 |pmid=39024193 |pmc=11257221 |doi=10.1371/journal.ppat.1012396 |doi-access=free }}</ref> Preliminary evidence supporting the notion that prions can be transmitted through use of urine-derived [[human menopausal gonadotropin]], administered for the treatment of [[infertility]], was published in 2011.<ref name="pmid21448279">{{cite journal |vauthors=Van Dorsselaer A, Carapito C, Delalande F, Schaeffer-Reiss C, Thierse D, Diemer H, McNair DS, Krewski D, Cashman NR |title=Detection of prion protein in urine-derived injectable fertility products by a targeted proteomic approach |journal=PLOS ONE |volume=6 |issue=3 |pages=e17815 |date=March 2011 |pmid=21448279 |pmc=3063168 |doi=10.1371/journal.pone.0017815 |bibcode=2011PLoSO...617815V |doi-access=free}}</ref>
+A [[University of California]] research team has provided evidence for the theory that infection can occur from prions in manure.<ref>{{cite journal | vauthors = Tamgüney G, Miller MW, Wolfe LL, Sirochman TM, Glidden DV, Palmer C, Lemus A, DeArmond SJ, Prusiner SB | title = Asymptomatic deer excrete infectious prions in faeces | journal = Nature | volume = 461 | issue = 7263 | pages = 529–532 | date = September 2009 | pmid = 19741608 | pmc = 3186440 | doi = 10.1038/nature08289 | bibcode = 2009Natur.461..529T }}</ref> And, since manure is present in many areas surrounding water reservoirs, as well as used on many crop fields, it raises the possibility of widespread transmission. Although it was initially reported in January 2011 that researchers had discovered prions spreading through airborne transmission on [[aerosol]] particles in an [[animal testing]] experiment focusing on [[scrapie]] infection in [[laboratory mice]],<ref>{{cite journal | vauthors = Haybaeck J, Heikenwalder M, Klevenz B, Schwarz P, Margalith I, Bridel C, Mertz K, Zirdum E, Petsch B, Fuchs TJ, Stitz L, Aguzzi A | title = Aerosols transmit prions to immunocompetent and immunodeficient mice | journal = PLoS Pathogens | volume = 7 | issue = 1 | pages = e1001257 | date = January 2011 | pmid = 21249178 | pmc = 3020930 | doi = 10.1371/journal.ppat.1001257 | doi-access = free }}{{Retracted|doi=10.1371/journal.ppat.1012396|pmid=39024193}}<br />Lay summary: {{cite web | vauthors = Mackenzie D |date=January 13, 2011 |title=Prion disease can spread through air |url=https://www.newscientist.com/article/dn19971-prion-disease-can-spread-through-air |url-access=registration |website=New Scientist}}</ref> this report was retracted in 2024.<ref>{{cite journal | vauthors = Haybaeck J, Heikenwalder M, Klevenz B, Schwarz P, Margalith I, Bridel C, Mertz K, Zirdum E, Petsch B, Fuchs TJ, Stitz L, Aguzzi A | title = Retraction: Aerosols Transmit Prions to Immunocompetent and Immunodeficient Mice | journal = PLoS Pathogens | volume = 20 | issue = 7 | pages = e1012396 | date = July 2024 | pmid = 39024193 | pmc = 11257221 | doi = 10.1371/journal.ppat.1012396 | doi-access = free }}</ref> Preliminary evidence supporting the notion that prions can be transmitted through use of urine-derived [[human menopausal gonadotropin]], administered for the treatment of [[infertility]], was published in 2011.<ref name="pmid21448279">{{cite journal | vauthors = Van Dorsselaer A, Carapito C, Delalande F, Schaeffer-Reiss C, Thierse D, Diemer H, McNair DS, Krewski D, Cashman NR | title = Detection of prion protein in urine-derived injectable fertility products by a targeted proteomic approach | journal = PloS One | volume = 6 | issue = 3 | pages = e17815 | date = March 2011 | pmid = 21448279 | pmc = 3063168 | doi = 10.1371/journal.pone.0017815 | doi-access = free | bibcode = 2011PLoSO...617815V }}</ref>
 ==== Prions in plants ====
-In 2015, researchers at [[The University of Texas Health Science Center at Houston]] found that plants can be a vector for prions. When researchers fed hamsters grass that grew on ground where a deer that died with [[chronic wasting disease]] (CWD) was buried, the hamsters became ill with CWD, suggesting that prions can bind to plants, which then take them up into the leaf and stem structure, where they can be eaten by herbivores, thus completing the cycle. It is thus possible that there is a progressively accumulating number of prions in the environment.<ref>{{cite news |vauthors=Beecher C |url=http://www.foodsafetynews.com/2015/06/researchers-make-surprising-discovery-about-spread-of-chronic-wasting-disease/ |title=Surprising' Discovery Made About Chronic Wasting Disease |work=[[Food Safety News]] |date=June 1, 2015 |access-date=2016-04-08 |archive-date=2016-04-28 |archive-url=https://web.archive.org/web/20160428055600/http://www.foodsafetynews.com/2015/06/researchers-make-surprising-discovery-about-spread-of-chronic-wasting-disease/ |url-status=live }}</ref><ref>{{cite journal | vauthors = Pritzkow S, Morales R, Moda F, Khan U, Telling GC, Hoover E, Soto C | title = Grass plants bind, retain, uptake, and transport infectious prions | journal = Cell Reports | volume = 11 | issue = 8 | pages = 1168–75 | date = May 2015 | pmid = 25981035 | pmc = 4449294 | doi = 10.1016/j.celrep.2015.04.036 }}</ref>
+In 2015, researchers at [[The University of Texas Health Science Center at Houston]] found that plants can be a vector for prions. When researchers fed hamsters grass that grew on ground where a deer that died with [[chronic wasting disease]] (CWD) was buried, the hamsters became ill with CWD, suggesting that prions can bind to plants, which then take them up into the leaf and stem structure, where they can be eaten by herbivores, thus completing the cycle. It is thus possible that there is a progressively accumulating number of prions in the environment.<ref>{{cite news |vauthors=Beecher C |url=http://www.foodsafetynews.com/2015/06/researchers-make-surprising-discovery-about-spread-of-chronic-wasting-disease/ |title=Surprising' Discovery Made About Chronic Wasting Disease |work=[[Food Safety News]] |date=June 1, 2015 |access-date=2016-04-08 |archive-date=2016-04-28 |archive-url=https://web.archive.org/web/20160428055600/http://www.foodsafetynews.com/2015/06/researchers-make-surprising-discovery-about-spread-of-chronic-wasting-disease/ |url-status=live }}</ref><ref>{{cite journal | vauthors = Pritzkow S, Morales R, Moda F, Khan U, Telling GC, Hoover E, Soto C | title = Grass plants bind, retain, uptake, and transport infectious prions | journal = Cell Reports | volume = 11 | issue = 8 | pages = 1168–1175 | date = May 2015 | pmid = 25981035 | pmc = 4449294 | doi = 10.1016/j.celrep.2015.04.036 }}</ref>
 === Sterilization ===
-Infectious particles possessing [[nucleic acid]] are dependent upon it to direct their continued replication. Prions, however, are infectious by their effect on normal versions of the protein. Sterilizing prions, therefore, requires the [[denaturation (biochemistry)|denaturation]] of the protein to a state in which the molecule is no longer able to induce the abnormal folding of normal proteins. In general, prions are quite resistant to [[protease]]s, heat, [[ionizing radiation]], and [[formaldehyde]] treatments,<ref>{{cite journal | vauthors = Qin K, O'Donnell M, Zhao RY | s2cid = 28822120 | title = Doppel: more rival than double to prion | journal = Neuroscience | volume = 141 | issue = 1 | pages = 1–8 | date = August 2006 | pmid = 16781817 | doi = 10.1016/j.neuroscience.2006.04.057 }}</ref> although their infectivity can be reduced by such treatments. Effective prion decontamination relies upon protein [[hydrolysis]] or reduction or destruction of [[protein tertiary structure]]. Examples include [[sodium hypochlorite]], [[sodium hydroxide]], and strongly acidic [[detergent]]s such as LpH.<ref>{{cite journal | vauthors = Race RE, Raymond GJ | title = Inactivation of transmissible spongiform encephalopathy (prion) agents by environ LpH | journal = Journal of Virology | volume = 78 | issue = 4 | pages = 2164–65 | date = February 2004 | pmid = 14747583 | pmc = 369477 | doi = 10.1128/JVI.78.4.2164-2165.2004 }}</ref>
+Infectious particles possessing [[nucleic acid]] are dependent upon it to direct their continued replication. Prions, however, are infectious by their effect on normal versions of the protein. Sterilizing prions, therefore, requires the [[denaturation (biochemistry)|denaturation]] of the protein to a state in which the molecule is no longer able to induce the abnormal folding of normal proteins. In general, prions are quite resistant to [[protease]]s, heat, [[ionizing radiation]], and [[formaldehyde]] treatments,<ref>{{cite journal | vauthors = Qin K, O'Donnell M, Zhao RY | title = Doppel: more rival than double to prion | journal = Neuroscience | volume = 141 | issue = 1 | pages = 1–8 | date = August 2006 | pmid = 16781817 | doi = 10.1016/j.neuroscience.2006.04.057 | s2cid = 28822120 }}</ref> although their infectivity can be reduced by such treatments. Effective prion decontamination relies upon protein [[hydrolysis]] or reduction or destruction of [[protein tertiary structure]]. Examples include [[sodium hypochlorite]], [[sodium hydroxide]], and strongly acidic [[detergent]]s such as LpH.<ref>{{cite journal | vauthors = Race RE, Raymond GJ | title = Inactivation of transmissible spongiform encephalopathy (prion) agents by environ LpH | journal = Journal of Virology | volume = 78 | issue = 4 | pages = 2164–2165 | date = February 2004 | pmid = 14747583 | pmc = 369477 | doi = 10.1128/JVI.78.4.2164-2165.2004 }}</ref>
 The [[World Health Organization]] recommends any of the following three procedures for the sterilization of all heat-resistant surgical instruments to ensure that they are not contaminated with prions:
@@ Line 157: / Line 157: @@
 # Immerse in [[Equivalent concentration|1N]]&nbsp;sodium hydroxide and place in a [[Autoclave#Air removal|gravity-displacement autoclave]] at 121&nbsp;°C for 30&nbsp;minutes; clean; rinse in water; and then perform routine sterilization processes.
 # Immerse in 1N&nbsp;sodium hypochlorite (20,000&nbsp;parts per million available chlorine) for 1&nbsp;hour; transfer instruments to water; heat in a gravity-displacement autoclave at 121&nbsp;°C for 1&nbsp;hour; clean; and then perform routine sterilization processes.
-# Immerse in 1N&nbsp;sodium hydroxide or sodium hypochlorite (20,000&nbsp;parts per million available chlorine) for 1&nbsp;hour; remove and rinse in water, then transfer to an open pan and heat in a gravity-displacement (121&nbsp;°C) or in a porous-load (134&nbsp;°C) autoclave for 1&nbsp;hour; clean; and then perform routine sterilization processes.<ref>{{cite journal | vauthors = Sutton JM, Dickinson J, Walker JT, Raven ND | title = Methods to minimize the risks of Creutzfeldt–Jakob disease transmission by surgical procedures: where to set the standard? | journal = Clinical Infectious Diseases | volume = 43 | issue = 6 | pages = 757–64 | date = September 2006 | pmid = 16912952 | doi = 10.1086/507030 | doi-access = free }}</ref>
+# Immerse in 1N&nbsp;sodium hydroxide or sodium hypochlorite (20,000&nbsp;parts per million available chlorine) for 1&nbsp;hour; remove and rinse in water, then transfer to an open pan and heat in a gravity-displacement (121&nbsp;°C) or in a porous-load (134&nbsp;°C) autoclave for 1&nbsp;hour; clean; and then perform routine sterilization processes.<ref>{{cite journal | vauthors = Sutton JM, Dickinson J, Walker JT, Raven ND | title = Methods to minimize the risks of Creutzfeldt-Jakob disease transmission by surgical procedures: where to set the standard? | journal = Clinical Infectious Diseases | volume = 43 | issue = 6 | pages = 757–764 | date = September 2006 | pmid = 16912952 | doi = 10.1086/507030 | doi-access = free }}</ref>
-{{convert|134|C}} for 18 minutes in a pressurized steam [[autoclave]] has been found to be somewhat effective in deactivating the agent of disease.<ref>{{cite journal | vauthors = Collins SJ, Lawson VA, Masters CL | s2cid = 23212525 | title = Transmissible spongiform encephalopathies | journal = Lancet | volume = 363 | issue = 9402 | pages = 51–61 | date = January 2004 | pmid = 14723996 | doi = 10.1016/S0140-6736(03)15171-9 }}</ref><ref name="pmid10716712">{{cite journal | vauthors = Brown P, Rau EH, Johnson BK, Bacote AE, Gibbs CJ, Gajdusek DC | title = New studies on the heat resistance of hamster-adapted scrapie agent: threshold survival after ashing at 600 degrees C suggests an inorganic template of replication | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 97 | issue = 7 | pages = 3418–21 | date = March 2000 | pmid = 10716712 | pmc = 16254 | doi = 10.1073/pnas.050566797 | bibcode = 2000PNAS...97.3418B | doi-access = free }}</ref> [[Ozone]] sterilization is currently being studied as a potential method for prion denaturation and deactivation.<ref>{{cite web | url=http://www.hpa.org.uk/hpa/news/articles/press_releases/2005/050414_ozone_sterilizer.htm | title=Ozone Sterilization | date=2005-04-14 | publisher=UK Health Protection Agency | access-date=2010-02-28 |archive-url = https://web.archive.org/web/20070210204514/http://www.hpa.org.uk/hpa/news/articles/press_releases/2005/050414_ozone_sterilizer.htm |archive-date=February 10, 2007 }}</ref> Other approaches being developed include [[thiourea]]-[[urea]] treatment, [[guanidinium chloride]] treatment,<ref>{{cite journal | vauthors = Botsios S, Tittman S, [[Laura Manuelidis|Manuelidis L]] | title = Rapid chemical decontamination of infectious CJD and scrapie particles parallels treatments known to disrupt microbes and biofilms | journal = Virulence | volume = 6 | issue = 8 | pages = 787–801 | date = 2015 | pmid = 26556670 | pmc = 4826107 | doi = 10.1080/21505594.2015.1098804 }}</ref> and special heat-resistant [[subtilisin]] combined with heat and detergent.<ref>{{cite journal | vauthors = Koga Y, Tanaka S, Sakudo A, Tobiume M, Aranishi M, Hirata A, Takano K, Ikuta K, Kanaya S | display-authors = 6 | title = Proteolysis of abnormal prion protein with a thermostable protease from Thermococcus kodakarensis KOD1 | journal = Applied Microbiology and Biotechnology | volume = 98 | issue = 5 | pages = 2113–2120 | date = March 2014 | pmid = 23880875 | doi = 10.1007/s00253-013-5091-7 | s2cid = 2677641 }}</ref> A method sufficient for sterilizing prions on one material may fail on another.<ref>{{cite journal | vauthors = Eraña H, Pérez-Castro MÁ, García-Martínez S, Charco JM, López-Moreno R, Díaz-Dominguez CM, Barrio T, González-Miranda E, Castilla J | display-authors = 6 | title = A Novel, Reliable and Highly Versatile Method to Evaluate Different Prion Decontamination Procedures | journal = Frontiers in Bioengineering and Biotechnology | volume = 8 | pages = 589182 | date = 2020 | pmid = 33195153 | pmc = 7658626 | doi = 10.3389/fbioe.2020.589182 | doi-access = free }}</ref>
+{{convert|134|C}} for 18 minutes in a pressurized steam [[autoclave]] has been found to be somewhat effective in deactivating the agent of disease.<ref>{{cite journal | vauthors = Collins SJ, Lawson VA, Masters CL | title = Transmissible spongiform encephalopathies | journal = Lancet | volume = 363 | issue = 9402 | pages = 51–61 | date = January 2004 | pmid = 14723996 | doi = 10.1016/S0140-6736(03)15171-9 | s2cid = 23212525 }}</ref><ref name="pmid10716712">{{cite journal | vauthors = Brown P, Rau EH, Johnson BK, Bacote AE, Gibbs CJ, Gajdusek DC | title = New studies on the heat resistance of hamster-adapted scrapie agent: threshold survival after ashing at 600 degrees C suggests an inorganic template of replication | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 97 | issue = 7 | pages = 3418–3421 | date = March 2000 | pmid = 10716712 | pmc = 16254 | doi = 10.1073/pnas.050566797 | doi-access = free | bibcode = 2000PNAS...97.3418B }}</ref> [[Ozone]] sterilization is currently being studied as a potential method for prion denaturation and deactivation.<ref>{{cite web | url=http://www.hpa.org.uk/hpa/news/articles/press_releases/2005/050414_ozone_sterilizer.htm | title=Ozone Sterilization | date=2005-04-14 | publisher=UK Health Protection Agency | access-date=2010-02-28 |archive-url = https://web.archive.org/web/20070210204514/http://www.hpa.org.uk/hpa/news/articles/press_releases/2005/050414_ozone_sterilizer.htm |archive-date=February 10, 2007 }}</ref> Other approaches being developed include [[thiourea]]-[[urea]] treatment, [[guanidinium chloride]] treatment,<ref>{{cite journal | vauthors = Botsios S, Tittman S, Manuelidis L | title = Rapid chemical decontamination of infectious CJD and scrapie particles parallels treatments known to disrupt microbes and biofilms | journal = Virulence | volume = 6 | issue = 8 | pages = 787–801 | date = 2015 | pmid = 26556670 | pmc = 4826107 | doi = 10.1080/21505594.2015.1098804 }}</ref> and special heat-resistant [[subtilisin]] combined with heat and detergent.<ref>{{cite journal | vauthors = Koga Y, Tanaka S, Sakudo A, Tobiume M, Aranishi M, Hirata A, Takano K, Ikuta K, Kanaya S | title = Proteolysis of abnormal prion protein with a thermostable protease from Thermococcus kodakarensis KOD1 | journal = Applied Microbiology and Biotechnology | volume = 98 | issue = 5 | pages = 2113–2120 | date = March 2014 | pmid = 23880875 | doi = 10.1007/s00253-013-5091-7 | s2cid = 2677641 }}</ref> A method sufficient for sterilizing prions on one material may fail on another.<ref>{{cite journal | vauthors = Eraña H, Pérez-Castro MÁ, García-Martínez S, Charco JM, López-Moreno R, Díaz-Dominguez CM, Barrio T, González-Miranda E, Castilla J | title = A Novel, Reliable and Highly Versatile Method to Evaluate Different Prion Decontamination Procedures | journal = Frontiers in Bioengineering and Biotechnology | volume = 8 | pages = 589182 | date = 2020 | pmid = 33195153 | pmc = 7658626 | doi = 10.3389/fbioe.2020.589182 | doi-access = free }}</ref>
-Renaturation of a completely denatured prion to infectious status has not yet been achieved; however, partially denatured prions can be renatured to an infective status under certain artificial conditions.<ref>{{cite journal | vauthors = Weissmann C, Enari M, Klöhn PC, Rossi D, Flechsig E | title = Transmission of prions | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = Suppl 4 | pages = 16378–83 | date = December 2002 | pmid = 12181490 | pmc = 139897 | doi = 10.1073/pnas.172403799 | bibcode = 2002PNAS...9916378W | doi-access = free }}</ref>
+Renaturation of a completely denatured prion to infectious status has not yet been achieved; however, partially denatured prions can be renatured to an infective status under certain artificial conditions.<ref>{{cite journal | vauthors = Weissmann C, Enari M, Klöhn PC, Rossi D, Flechsig E | title = Transmission of prions | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = s 4 | pages = 16378–16383 | date = December 2002 | pmid = 12181490 | pmc = 139897 | doi = 10.1073/pnas.172403799 | doi-access = free | bibcode = 2002PNAS...9916378W }}</ref>
 === Degradation resistance in nature ===
-Overwhelming evidence shows that prions resist degradation and persist in the environment for years, and [[protease]]s do not degrade them. Experimental evidence shows that ''unbound'' prions degrade over time, while soil-bound prions remain at stable or increasing levels, suggesting that prions likely accumulate in the environment.<ref>{{cite journal | vauthors = Zabel M, Ortega A | title = The Ecology of Prions | journal = Microbiology and Molecular Biology Reviews | volume = 81 | issue = 3 | date = September 2017 | pmid = 28566466 | pmc = 5584314 | doi = 10.1128/MMBR.00001-17 }}</ref><ref>{{cite journal | vauthors = Kuznetsova A, Cullingham C, McKenzie D, Aiken JM | title = Soil humic acids degrade CWD prions and reduce infectivity | journal = PLOS Pathogens | volume = 14 | issue = 11 | pages = e1007414 | date = November 2018 | pmid = 30496301 | pmc = 6264147 | doi = 10.1371/journal.ppat.1007414 | doi-access = free }}</ref> One 2015 study by US scientists found that repeated drying and wetting may render soil bound prions less infectious, although this was dependent on the soil type they were bound to.<ref>{{cite journal | vauthors = Yuan Q, Eckland T, Telling G, Bartz J, Bartelt-Hunt S | title = Mitigation of prion infectivity and conversion capacity by a simulated natural process--repeated cycles of drying and wetting | journal = PLOS Pathogens | volume = 11 | issue = 2 | pages = e1004638 | date = February 2015 | pmid = 25665187 | pmc = 4335458 | doi = 10.1371/journal.ppat.1004638 | doi-access = free }}</ref>
+Overwhelming evidence shows that prions resist degradation and persist in the environment for years, and [[protease]]s do not degrade them. Experimental evidence shows that ''unbound'' prions degrade over time, while soil-bound prions remain at stable or increasing levels, suggesting that prions likely accumulate in the environment.<ref>{{cite journal | vauthors = Zabel M, Ortega A | title = The Ecology of Prions | journal = Microbiology and Molecular Biology Reviews | volume = 81 | issue = 3 | date = September 2017 | pmid = 28566466 | pmc = 5584314 | doi = 10.1128/MMBR.00001-17 }}</ref><ref>{{cite journal | vauthors = Kuznetsova A, Cullingham C, McKenzie D, Aiken JM | title = Soil humic acids degrade CWD prions and reduce infectivity | journal = PLoS Pathogens | volume = 14 | issue = 11 | pages = e1007414 | date = November 2018 | pmid = 30496301 | pmc = 6264147 | doi = 10.1371/journal.ppat.1007414 | doi-access = free }}</ref> One 2015 study by US scientists found that repeated drying and wetting may render soil bound prions less infectious, although this was dependent on the soil type they were bound to.<ref>{{cite journal | vauthors = Yuan Q, Eckland T, Telling G, Bartz J, Bartelt-Hunt S | title = Mitigation of prion infectivity and conversion capacity by a simulated natural process--repeated cycles of drying and wetting | journal = PLoS Pathogens | volume = 11 | issue = 2 | pages = e1004638 | date = February 2015 | pmid = 25665187 | pmc = 4335458 | doi = 10.1371/journal.ppat.1004638 | doi-access = free }}</ref>
 === Degradation by living beings ===
-More recent studies suggest scrapie prions can be degraded by diverse cellular machinery. Inhibition of autophagy accelerates prion accumulation whereas encouragement of autophagy promotes prion clearance.<ref name=":1">{{Cite journal |last1=López-Pérez |first1=Óscar |last2=Badiola |first2=Juan José |last3=Bolea |first3=Rosa |last4=Ferrer |first4=Isidro |last5=Llorens |first5=Franc |last6=Martín-Burriel |first6=Inmaculada |date=2020-08-27 |title=An Update on Autophagy in Prion Diseases |journal=Frontiers in Bioengineering and Biotechnology |language=English |volume=8 |page=975 |doi=10.3389/fbioe.2020.00975 |doi-access=free |pmid=32984276 |pmc=7481332 |issn=2296-4185}}</ref> The [[Proteasome|ubiquitin proteasome system]] appears to be able to degrade small enough aggregates.<ref name=":1" /> In addition, keratinase from [[Bacillus licheniformis|''B. licheniformis'']],<ref>{{Cite journal |last1=Langeveld |first1=Jan P. M. |last2=Wang |first2=Jeng-Jie |last3=Van de Wiel |first3=Dick F. M. |last4=Shih |first4=Giles C. |last5=Garssen |first5=G. Jan |last6=Bossers |first6=Alex |last7=Shih |first7=Jason C. H. |date=2003-12-01 |title=Enzymatic degradation of prion protein in brain stem from infected cattle and sheep |url=https://pubmed.ncbi.nlm.nih.gov/14639552/ |journal=The Journal of Infectious Diseases |volume=188 |issue=11 |pages=1782–1789 |doi=10.1086/379664 |issn=0022-1899 |pmid=14639552}}</ref><ref>{{Cite journal |last1=Okoroma |first1=Emeka A. |last2=Purchase |first2=Diane |last3=Garelick |first3=Hemda |last4=Morris |first4=Roger |last5=Neale |first5=Michael H. |last6=Windl |first6=Otto |last7=Abiola |first7=Oduola O. |date=2013-07-16 |title=Enzymatic Formulation Capable of Degrading Scrapie Prion under Mild Digestion Conditions |journal=PLOS ONE |language=en |volume=8 |issue=7 |pages=e68099 |doi=10.1371/journal.pone.0068099 |doi-access=free |issn=1932-6203 |pmc=3712960 |pmid=23874511|bibcode=2013PLoSO...868099O }}</ref> alkaline [[serine protease]] from ''Streptomyces sp'',<ref>{{Cite journal |last1=Hui |first1=Zhao |last2=Doi |first2=Hiroyasu |last3=Kanouchi |first3=Hiroaki |last4=Matsuura |first4=Yuichi |last5=Mohri |first5=Shiro |last6=Nonomura |first6=Yoshiaki |last7=Oka |first7=Tatsuzo |date=2004-08-13 |title=Alkaline serine protease produced by Streptomyces sp. degrades PrPSc |url=https://www.sciencedirect.com/science/article/abs/pii/S0006291X04013774 |journal=Biochemical and Biophysical Research Communications |volume=321 |issue=1 |pages=45–50 |doi=10.1016/j.bbrc.2004.06.100 |pmid=15358213 |issn=0006-291X}}</ref> [[subtilisin]]-like pernisine from ''[[Aeropyrum pernix]]'',<ref>{{Cite journal |last1=Snajder |first1=Marko |last2=Vilfan |first2=Tanja |last3=Cernilec |first3=Maja |last4=Rupreht |first4=Ruth |last5=Popović |first5=Mara |last6=Juntes |first6=Polona |last7=Serbec |first7=Vladka Čurin |last8=Ulrih |first8=Nataša Poklar |date=2012 |title=Enzymatic degradation of PrPSc by a protease secreted from Aeropyrum pernix K1 |journal=PLOS ONE |volume=7 |issue=6 |pages=e39548 |doi=10.1371/journal.pone.0039548 |doi-access=free |issn=1932-6203 |pmc=3386259 |pmid=22761822|bibcode=2012PLoSO...739548S }}</ref> alkaline protease from ''[[Nocardiopsis]] sp'',<ref>{{Cite journal |last1=Mitsuiki |first1=Shinji |last2=Hui |first2=Zhao |last3=Matsumoto |first3=Daishi |last4=Sakai |first4=Masashi |last5=Moriyama |first5=Yasushi |last6=Furukawa |first6=Kensuke |last7=Kanouchi |first7=Hiroaki |last8=Oka |first8=Tatsuzo |date=2006-05-23 |title=Degradation of PrP Sc by Keratinolytic Protease from Nocardiopsis sp. TOA-1 |url=https://academic.oup.com/bbb/article/70/5/1246-1248/5953917 |journal=Bioscience, Biotechnology, and Biochemistry |language=en |volume=70 |issue=5 |pages=1246–1248 |doi=10.1271/bbb.70.1246 |pmid=16717429 |issn=0916-8451}}</ref> [[nattokinase]] from ''[[Bacillus subtilis|B. subtilis]]'',<ref>{{Cite journal |last1=Hsu |first1=Ruei-Lin |last2=Lee |first2=Kung-Ta |last3=Wang |first3=Jung-Hao |last4=Lee |first4=Lily Y.-L. |last5=Chen |first5=Rita P.-Y. |date=2009-01-28 |title=Amyloid-Degrading Ability of Nattokinase from Bacillus subtilis Natto |url=https://pubs.acs.org/doi/10.1021/jf803072r |journal=Journal of Agricultural and Food Chemistry |language=en |volume=57 |issue=2 |pages=503–508 |doi=10.1021/jf803072r |pmid=19117402 |issn=0021-8561}}</ref> engineered subtilisins from ''B. lentus''<ref>{{Cite journal |last1=Booth |first1=Clarissa J. |last2=Johnson |first2=Christopher J. |last3=Pedersen |first3=Joel A. |date=2013-04-01 |title=Microbial and enzymatic inactivation of prions in soil environments |url=https://linkinghub.elsevier.com/retrieve/pii/S0038071713000035 |journal=Soil Biology and Biochemistry |volume=59 |pages=1–15 |doi=10.1016/j.soilbio.2012.12.016 |bibcode=2013SBiBi..59....1B |issn=0038-0717}}</ref><ref>{{Cite journal |last1=Dickinson |first1=J. |last2=Murdoch |first2=H. |last3=Dennis |first3=M. J. |last4=Hall |first4=G. A. |last5=Bott |first5=R. |last6=Crabb |first6=W. D. |last7=Penet |first7=C. |last8=Sutton |first8=J. M. |last9=Raven |first9=N. D. H. |date=2009 |title=Decontamination of prion protein (BSE301V) using a genetically engineered protease |url=https://pubmed.ncbi.nlm.nih.gov/19201054/ |journal=The Journal of Hospital Infection |volume=72 |issue=1 |pages=65–70 |doi=10.1016/j.jhin.2008.12.007 |issn=1532-2939 |pmid=19201054}}</ref> and serine protease from three lichen species<ref>{{Cite journal |last1=Johnson |first1=Christopher J. |last2=Bennett |first2=James P. |last3=Biro |first3=Steven M. |last4=Duque-Velasquez |first4=Juan Camilo |last5=Rodriguez |first5=Cynthia M. |last6=Bessen |first6=Richard A. |last7=Rocke |first7=Tonie E. |date=2011-05-11 |title=Degradation of the Disease-Associated Prion Protein by a Serine Protease from Lichens |journal=PLOS ONE |language=en |volume=6 |issue=5 |pages=e19836 |doi=10.1371/journal.pone.0019836 |doi-access=free |issn=1932-6203 |pmc=3092769 |pmid=21589935|bibcode=2011PLoSO...619836J }}</ref> have been found to degrade PrP.
+More recent studies suggest scrapie prions can be degraded by diverse cellular machinery. Inhibition of autophagy accelerates prion accumulation whereas encouragement of autophagy promotes prion clearance.<ref name=":1">{{cite journal | vauthors = López-Pérez Ó, Badiola JJ, Bolea R, Ferrer I, Llorens F, Martín-Burriel I | title = An Update on Autophagy in Prion Diseases | language = English | journal = Frontiers in Bioengineering and Biotechnology | volume = 8 | pages = 975 | date = 2020-08-27 | pmid = 32984276 | pmc = 7481332 | doi = 10.3389/fbioe.2020.00975 | doi-access = free }}</ref> The [[Proteasome|ubiquitin proteasome system]] appears to be able to degrade small enough aggregates.<ref name=":1" /> In addition, keratinase from [[Bacillus licheniformis|''B. licheniformis'']],<ref>{{cite journal | vauthors = Langeveld JP, Wang JJ, Van de Wiel DF, Shih GC, Garssen GJ, Bossers A, Shih JC | title = Enzymatic degradation of prion protein in brain stem from infected cattle and sheep | journal = The Journal of Infectious Diseases | volume = 188 | issue = 11 | pages = 1782–1789 | date = December 2003 | pmid = 14639552 | doi = 10.1086/379664 }}</ref><ref>{{cite journal | vauthors = Okoroma EA, Purchase D, Garelick H, Morris R, Neale MH, Windl O, Abiola OO | title = Enzymatic formulation capable of degrading scrapie prion under mild digestion conditions | journal = PloS One | volume = 8 | issue = 7 | pages = e68099 | date = 2013-07-16 | pmid = 23874511 | pmc = 3712960 | doi = 10.1371/journal.pone.0068099 | doi-access = free | bibcode = 2013PLoSO...868099O }}</ref> alkaline [[serine protease]] from ''Streptomyces sp'',<ref>{{cite journal | vauthors = Hui Z, Doi H, Kanouchi H, Matsuura Y, Mohri S, Nonomura Y, Oka T | title = Alkaline serine protease produced by Streptomyces sp. degrades PrP(Sc) | journal = Biochemical and Biophysical Research Communications | volume = 321 | issue = 1 | pages = 45–50 | date = August 2004 | pmid = 15358213 | doi = 10.1016/j.bbrc.2004.06.100 }}</ref> [[subtilisin]]-like pernisine from ''[[Aeropyrum pernix]]'',<ref>{{cite journal | vauthors = Snajder M, Vilfan T, Cernilec M, Rupreht R, Popović M, Juntes P, Serbec VČ, Ulrih NP | title = Enzymatic degradation of PrPSc by a protease secreted from Aeropyrum pernix K1 | journal = PloS One | volume = 7 | issue = 6 | pages = e39548 | date = 2012 | pmid = 22761822 | pmc = 3386259 | doi = 10.1371/journal.pone.0039548 | doi-access = free | bibcode = 2012PLoSO...739548S }}</ref> alkaline protease from ''[[Nocardiopsis]] sp'',<ref>{{cite journal | vauthors = Mitsuiki S, Hui Z, Matsumoto D, Sakai M, Moriyama Y, Furukawa K, Kanouchi H, Oka T | title = Degradation of PrP(Sc) by keratinolytic protease from Nocardiopsis sp. TOA-1 | journal = Bioscience, Biotechnology, and Biochemistry | volume = 70 | issue = 5 | pages = 1246–1248 | date = May 2006 | pmid = 16717429 | doi = 10.1271/bbb.70.1246 }}</ref> [[nattokinase]] from ''[[Bacillus subtilis|B. subtilis]]'',<ref>{{cite journal | vauthors = Hsu RL, Lee KT, Wang JH, Lee LY, Chen RP | title = Amyloid-degrading ability of nattokinase from Bacillus subtilis natto | journal = Journal of Agricultural and Food Chemistry | volume = 57 | issue = 2 | pages = 503–508 | date = January 2009 | pmid = 19117402 | doi = 10.1021/jf803072r }}</ref> engineered subtilisins from ''B. lentus''<ref>{{Cite journal | vauthors = Booth CJ, Johnson CJ, Pedersen JA |date= April 2013 |title=Microbial and enzymatic inactivation of prions in soil environments |url=https://linkinghub.elsevier.com/retrieve/pii/S0038071713000035 |journal=Soil Biology and Biochemistry |volume=59 |pages=1–15 |doi=10.1016/j.soilbio.2012.12.016 |bibcode=2013SBiBi..59....1B |issn=0038-0717}}</ref><ref>{{cite journal | vauthors = Dickinson J, Murdoch H, Dennis MJ, Hall GA, Bott R, Crabb WD, Penet C, Sutton JM, Raven ND | title = Decontamination of prion protein (BSE301V) using a genetically engineered protease | journal = The Journal of Hospital Infection | volume = 72 | issue = 1 | pages = 65–70 | date = May 2009 | pmid = 19201054 | doi = 10.1016/j.jhin.2008.12.007 }}</ref> and serine protease from three lichen species<ref>{{cite journal | vauthors = Johnson CJ, Bennett JP, Biro SM, Duque-Velasquez JC, Rodriguez CM, Bessen RA, Rocke TE | title = Degradation of the disease-associated prion protein by a serine protease from lichens | journal = PloS One | volume = 6 | issue = 5 | pages = e19836 | date = May 2011 | pmid = 21589935 | pmc = 3092769 | doi = 10.1371/journal.pone.0019836 | doi-access = free | bibcode = 2011PLoSO...619836J }}</ref> have been found to degrade PrP.
 == Fungi ==
 {{Main|Fungal prion}}
-Proteins showing prion-type behavior are also found in some [[fungus|fungi]], which has been useful in helping to understand mammalian prions. [[Fungal prion]]s do not always cause disease in their hosts.<ref>{{cite journal | vauthors = Lindquist S, Krobitsch S, Li L, Sondheimer N | title = Investigating protein conformation-based inheritance and disease in yeast | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 356 | issue = 1406 | pages = 169–76 | date = February 2001 | pmid = 11260797 | pmc = 1088422 | doi = 10.1098/rstb.2000.0762 }}</ref> In yeast, protein refolding to the prion configuration is assisted by [[Chaperone (protein)|chaperone proteins]] such as [[Hsp104]].<ref name='Aguzzi'>{{cite journal | vauthors = Aguzzi A | title = Unraveling prion strains with cell biology and organic chemistry | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 1 | pages = 11–12 | date = January 2008 | pmid = 18172195 | pmc = 2224168 | doi = 10.1073/pnas.0710824105 | bibcode = 2008PNAS..105...11A | doi-access = free }}</ref> All known prions induce the formation of an [[amyloid]] fold, in which the protein polymerises into an aggregate consisting of tightly packed [[beta sheet]]s. Amyloid aggregates are fibrils, growing at their ends, and replicate when breakage causes two growing ends to become four growing ends. The [[incubation period]] of prion diseases is determined by the [[exponential growth]] rate associated with prion replication, which is a balance between the linear growth and the breakage of aggregates.<ref name="Masel 99">{{cite journal | vauthors = Masel J, Jansen VA, Nowak MA | title = Quantifying the kinetic parameters of prion replication | journal = Biophysical Chemistry | volume = 77 | issue = 2–3 | pages = 139–52 | date = March 1999 | pmid = 10326247 | doi = 10.1016/S0301-4622(99)00016-2 | citeseerx = 10.1.1.178.8812 }}</ref>
+Proteins showing prion-type behavior are also found in some [[fungus|fungi]], which has been useful in helping to understand mammalian prions. [[Fungal prion]]s do not always cause disease in their hosts.<ref>{{cite journal | vauthors = Lindquist S, Krobitsch S, Li L, Sondheimer N | title = Investigating protein conformation-based inheritance and disease in yeast | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 356 | issue = 1406 | pages = 169–176 | date = February 2001 | pmid = 11260797 | pmc = 1088422 | doi = 10.1098/rstb.2000.0762 }}</ref> In yeast, protein refolding to the prion configuration is assisted by [[Chaperone (protein)|chaperone proteins]] such as [[Hsp104]].<ref name='Aguzzi'>{{cite journal | vauthors = Aguzzi A | title = Unraveling prion strains with cell biology and organic chemistry | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 1 | pages = 11–12 | date = January 2008 | pmid = 18172195 | pmc = 2224168 | doi = 10.1073/pnas.0710824105 | doi-access = free | bibcode = 2008PNAS..105...11A }}</ref> All known prions induce the formation of an [[amyloid]] fold, in which the protein polymerises into an aggregate consisting of tightly packed [[beta sheet]]s. Amyloid aggregates are fibrils, growing at their ends, and replicate when breakage causes two growing ends to become four growing ends. The [[incubation period]] of prion diseases is determined by the [[exponential growth]] rate associated with prion replication, which is a balance between the linear growth and the breakage of aggregates.<ref name="Masel 99">{{cite journal | vauthors = Masel J, Jansen VA, Nowak MA | title = Quantifying the kinetic parameters of prion replication | journal = Biophysical Chemistry | volume = 77 | issue = 2-3 | pages = 139–152 | date = March 1999 | pmid = 10326247 | doi = 10.1016/S0301-4622(99)00016-2 | citeseerx = 10.1.1.178.8812 }}</ref>
-Fungal proteins exhibiting templated conformational change{{Explain|reason=this is gobbledygook jargon to the uninitiated|date=August 2018}} were discovered in the yeast ''[[Saccharomyces cerevisiae]]'' by [[Reed Wickner]] in the early 1990s. For their mechanistic similarity to mammalian prions, they were termed [[yeast prion]]s. Subsequent to this, a prion has also been found in the fungus ''[[Podospora anserina]]''. These prions behave similarly to PrP, but, in general, are nontoxic to their hosts. [[Susan Lindquist]]'s group at the [[Whitehead Institute]] has argued some of the fungal prions are not associated with any disease state, but may have a useful role; however, researchers at the NIH have also provided arguments suggesting that fungal prions could be considered a diseased state.<ref>{{cite journal | vauthors = Dong J, Bloom JD, Goncharov V, Chattopadhyay M, Millhauser GL, Lynn DG, Scheibel T, Lindquist S | title = Probing the role of PrP repeats in conformational conversion and amyloid assembly of chimeric yeast prions | journal = The Journal of Biological Chemistry | volume = 282 | issue = 47 | pages = 34204–12 | date = November 2007 | pmid = 17893150 | pmc = 2262835 | doi = 10.1074/jbc.M704952200 | doi-access = free }}</ref> There is evidence that fungal proteins have evolved specific functions that are beneficial to the microorganism that enhance their ability to adapt to their diverse environments.<ref>{{cite journal | vauthors = Newby GA, Lindquist S | title = Blessings in disguise: biological benefits of prion-like mechanisms | journal = Trends in Cell Biology | volume = 23 | issue = 6 | pages = 251–59 | date = June 2013 | pmid = 23485338 | doi = 10.1016/j.tcb.2013.01.007 | hdl = 1721.1/103966 | hdl-access = free }}</ref> Further, within yeasts, prions can act as vectors of [[Epigenetics|epigenetic]] inheritance, transferring traits to offspring without any [[Genome|genomic]] change.<ref>{{cite journal | vauthors = Halfmann R, Lindquist S | title = Epigenetics in the extreme: prions and the inheritance of environmentally acquired traits | journal = Science | volume = 330 | issue = 6004 | pages = 629–632 | date = October 2010 | pmid = 21030648 | doi = 10.1126/science.1191081 | bibcode = 2010Sci...330..629H | s2cid = 206527151 }}</ref><ref>{{cite journal | vauthors = Halfmann R, Jarosz DF, Jones SK, Chang A, Lancaster AK, Lindquist S | title = Prions are a common mechanism for phenotypic inheritance in wild yeasts | journal = Nature | volume = 482 | issue = 7385 | pages = 363–368 | date = February 2012 | pmid = 22337056 | pmc = 3319070 | doi = 10.1038/nature10875 | bibcode = 2012Natur.482..363H }}</ref>
+Fungal proteins exhibiting templated conformational change{{Explain|reason=this is gobbledygook jargon to the uninitiated|date=August 2018}} were discovered in the yeast ''[[Saccharomyces cerevisiae]]'' by [[Reed Wickner]] in the early 1990s. For their mechanistic similarity to mammalian prions, they were termed [[yeast prion]]s. Subsequent to this, a prion has also been found in the fungus ''[[Podospora anserina]]''. These prions behave similarly to PrP, but, in general, are nontoxic to their hosts. [[Susan Lindquist]]'s group at the [[Whitehead Institute]] has argued some of the fungal prions are not associated with any disease state, but may have a useful role; however, researchers at the NIH have also provided arguments suggesting that fungal prions could be considered a diseased state.<ref>{{cite journal | vauthors = Dong J, Bloom JD, Goncharov V, Chattopadhyay M, Millhauser GL, Lynn DG, Scheibel T, Lindquist S | title = Probing the role of PrP repeats in conformational conversion and amyloid assembly of chimeric yeast prions | journal = The Journal of Biological Chemistry | volume = 282 | issue = 47 | pages = 34204–34212 | date = November 2007 | pmid = 17893150 | pmc = 2262835 | doi = 10.1074/jbc.M704952200 | doi-access = free }}</ref> There is evidence that fungal proteins have evolved specific functions that are beneficial to the microorganism that enhance their ability to adapt to their diverse environments.<ref>{{cite journal | vauthors = Newby GA, Lindquist S | title = Blessings in disguise: biological benefits of prion-like mechanisms | journal = Trends in Cell Biology | volume = 23 | issue = 6 | pages = 251–259 | date = June 2013 | pmid = 23485338 | doi = 10.1016/j.tcb.2013.01.007 | hdl-access = free | hdl = 1721.1/103966 }}</ref> Further, within yeasts, prions can act as vectors of [[Epigenetics|epigenetic]] inheritance, transferring traits to offspring without any [[Genome|genomic]] change.<ref>{{cite journal | vauthors = Halfmann R, Lindquist S | title = Epigenetics in the extreme: prions and the inheritance of environmentally acquired traits | journal = Science | volume = 330 | issue = 6004 | pages = 629–632 | date = October 2010 | pmid = 21030648 | doi = 10.1126/science.1191081 | s2cid = 206527151 | bibcode = 2010Sci...330..629H }}</ref><ref>{{cite journal | vauthors = Halfmann R, Jarosz DF, Jones SK, Chang A, Lancaster AK, Lindquist S | title = Prions are a common mechanism for phenotypic inheritance in wild yeasts | journal = Nature | volume = 482 | issue = 7385 | pages = 363–368 | date = February 2012 | pmid = 22337056 | pmc = 3319070 | doi = 10.1038/nature10875 | bibcode = 2012Natur.482..363H }}</ref>
 Research into [[fungal prion]]s has given strong support to the protein-only concept, since purified protein extracted from cells with a prion state has been demonstrated to convert the normal form of the protein into a misfolded form ''[[in vitro]]'', and in the process, preserve the information corresponding to different strains of the prion state. It has also shed some light on prion domains, which are regions in a protein that promote the conversion into a prion. Fungal prions have helped to suggest mechanisms of conversion that may apply to all prions, though fungal prions appear distinct from infectious mammalian prions in the lack of cofactor required for propagation. The characteristic prion domains may vary between species&nbsp;– e.g., characteristic fungal prion domains are not found in mammalian prions.{{citation needed|date=January 2023}}
@@ Line 242: / Line 242: @@
 | [ISP+]
 | Antisuppression
-| 2010<ref name="RogozaT">{{cite journal | vauthors = Rogoza T, Goginashvili A, Rodionova S, Ivanov M, Viktorovskaya O, Rubel A, Volkov K, Mironova L | title = Non-Mendelian determinant [ISP+] in yeast is a nuclear-residing prion form of the global transcriptional regulator Sfp1 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 | issue = 23 | pages = 10573–77 | date = June 2010 | pmid = 20498075 | pmc = 2890785 | doi = 10.1073/pnas.1005949107 | bibcode = 2010PNAS..10710573R | doi-access = free }}</ref>{{contradictory inline|Text did not say about this even as of 2012|date=November 2012}}
+| 2010<ref name="RogozaT">{{cite journal | vauthors = Rogoza T, Goginashvili A, Rodionova S, Ivanov M, Viktorovskaya O, Rubel A, Volkov K, Mironova L | title = Non-Mendelian determinant [ISP+] in yeast is a nuclear-residing prion form of the global transcriptional regulator Sfp1 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 | issue = 23 | pages = 10573–10577 | date = June 2010 | pmid = 20498075 | pmc = 2890785 | doi = 10.1073/pnas.1005949107 | doi-access = free | bibcode = 2010PNAS..10710573R }}</ref>{{contradictory inline|Text did not say about this even as of 2012|date=November 2012}}
 |}
 == Treatments ==
-There are no effective treatments for prion diseases.<ref name="pmid28961066">{{cite journal |vauthors=Aguzzi A, ((Lakkaraju AKK)), Frontzek K |title=Toward Therapy of Human Prion Diseases |journal=Annual Review of Pharmacology and Toxicology |volume=58 |pages=331–51 |date=January 2018 |issue=1 |pmid=28961066 |doi=10.1146/annurev-pharmtox-010617-052745 |url=https://www.zora.uzh.ch/id/eprint/141186/1/Aguzzi_et_al%3B_2017_revised.pdf |access-date=2020-03-05 |archive-date=2020-03-12 |archive-url=https://web.archive.org/web/20200312215409/https://www.zora.uzh.ch/id/eprint/141186/1/Aguzzi_et_al%3B_2017_revised.pdf |url-status=live }}</ref> Clinical trials in humans have not met with success and have been hampered by the rarity of prion diseases.<ref name="pmid28961066"/> Although some potential treatments have shown promise in the laboratory, none have been effective once the disease has commenced.<ref>{{cite web|url=http://www.prion.ucl.ac.uk/clinic-services/research/drug-treatments/|title=Prion Clinic – Drug treatments|date=13 September 2017 |access-date=2020-01-29|archive-date=2020-01-29|archive-url=https://web.archive.org/web/20200129093314/http://www.prion.ucl.ac.uk/clinic-services/research/drug-treatments/|url-status=live}}</ref>
+There are no effective treatments for prion diseases.<ref name="pmid28961066">{{cite journal | vauthors = Aguzzi A, Lakkaraju AK, Frontzek K | title = Toward Therapy of Human Prion Diseases | journal = Annual Review of Pharmacology and Toxicology | volume = 58 | issue = 1 | pages = 331–351 | date = January 2018 | pmid = 28961066 | doi = 10.1146/annurev-pharmtox-010617-052745 | url = https://www.zora.uzh.ch/id/eprint/141186/1/Aguzzi_et_al%3B_2017_revised.pdf | access-date = 2020-03-05 | url-status = live | archive-url = https://web.archive.org/web/20200312215409/https://www.zora.uzh.ch/id/eprint/141186/1/Aguzzi_et_al%3B_2017_revised.pdf | archive-date = 2020-03-12 }}</ref> Clinical trials in humans have not met with success and have been hampered by the rarity of prion diseases.<ref name="pmid28961066"/> Although some potential treatments have shown promise in the laboratory, none have been effective once the disease has commenced.<ref>{{cite web|url=http://www.prion.ucl.ac.uk/clinic-services/research/drug-treatments/|title=Prion Clinic – Drug treatments|date=13 September 2017 |access-date=2020-01-29|archive-date=2020-01-29|archive-url=https://web.archive.org/web/20200129093314/http://www.prion.ucl.ac.uk/clinic-services/research/drug-treatments/|url-status=live}}</ref>
 == In other diseases ==
-Prion-like domains have been found in a variety of other mammalian proteins. Some of these proteins have been implicated in the ontogeny of age-related neurodegenerative disorders such as [[amyotrophic lateral sclerosis]] (ALS), [[Frontotemporal lobar degeneration|frontotemporal lobar degeneration with ubiquitin-positive inclusions]] (FTLD-U), [[Alzheimer's disease]], [[Parkinson's disease]], and [[Huntington's disease]].<ref name="King 2012">{{cite journal | vauthors = King OD, Gitler AD, Shorter J | title = The tip of the iceberg: RNA-binding proteins with prion-like domains in neurodegenerative disease | journal = Brain Research | volume = 1462 | pages = 61–80 | date = June 2012 | pmid = 22445064 | pmc = 3372647 | doi = 10.1016/j.brainres.2012.01.016 }}</ref><ref name="Goedert"/><ref name="Olanow"/> They are also implicated in some forms of systemic [[amyloidosis]] including [[AA amyloidosis]] that develops in humans and animals with inflammatory and infectious diseases such as [[tuberculosis]], [[Crohn's disease]], [[rheumatoid arthritis]], and [[HIV/AIDS]]. AA amyloidosis, like prion disease, may be transmissible.<ref>{{cite journal | vauthors = Murakami T, Ishiguro N, Higuchi K | title = Transmission of systemic AA amyloidosis in animals | journal = Veterinary Pathology | volume = 51 | issue = 2 | pages = 363–71 | date = March 2014 | pmid = 24280941 | doi = 10.1177/0300985813511128 | doi-access = free | url = https://soar-ir.repo.nii.ac.jp/record/3728/files/Transmission_Systemic_AA_Amyloidosis_Animals.pdf }}</ref> This has given rise to the 'prion paradigm', where otherwise harmless proteins can be converted to a pathogenic form by a small number of misfolded, nucleating proteins.<ref name="Jucker 13">{{cite journal | vauthors = [[Mathias Jucker (neuroscientist)|Jucker M]], Walker LC | title = Self-propagation of pathogenic protein aggregates in neurodegenerative diseases | journal = Nature | volume = 501 | issue = 7465 | pages = 45–51 | date = September 2013 | pmid = 24005412 | pmc = 3963807 | doi = 10.1038/nature12481 | bibcode = 2013Natur.501...45J }}</ref>
+Prion-like domains have been found in a variety of other mammalian proteins. Some of these proteins have been implicated in the ontogeny of age-related neurodegenerative disorders such as [[amyotrophic lateral sclerosis]] (ALS), [[Frontotemporal lobar degeneration|frontotemporal lobar degeneration with ubiquitin-positive inclusions]] (FTLD-U), [[Alzheimer's disease]], [[Parkinson's disease]], and [[Huntington's disease]].<ref name="King 2012">{{cite journal | vauthors = King OD, Gitler AD, Shorter J | title = The tip of the iceberg: RNA-binding proteins with prion-like domains in neurodegenerative disease | journal = Brain Research | volume = 1462 | pages = 61–80 | date = June 2012 | pmid = 22445064 | pmc = 3372647 | doi = 10.1016/j.brainres.2012.01.016 }}</ref><ref name="Goedert"/><ref name="Olanow"/> They are also implicated in some forms of systemic [[amyloidosis]] including [[AA amyloidosis]] that develops in humans and animals with inflammatory and infectious diseases such as [[tuberculosis]], [[Crohn's disease]], [[rheumatoid arthritis]], and [[HIV/AIDS]]. AA amyloidosis, like prion disease, may be transmissible.<ref>{{cite journal | vauthors = Murakami T, Ishiguro N, Higuchi K | title = Transmission of systemic AA amyloidosis in animals | journal = Veterinary Pathology | volume = 51 | issue = 2 | pages = 363–371 | date = March 2014 | pmid = 24280941 | doi = 10.1177/0300985813511128 | doi-access = free }}</ref> This has given rise to the 'prion paradigm', where otherwise harmless proteins can be converted to a pathogenic form by a small number of misfolded, nucleating proteins.<ref name="Jucker 13">{{cite journal | vauthors = Jucker M, Walker LC | title = Self-propagation of pathogenic protein aggregates in neurodegenerative diseases | journal = Nature | volume = 501 | issue = 7465 | pages = 45–51 | date = September 2013 | pmid = 24005412 | pmc = 3963807 | doi = 10.1038/nature12481 | bibcode = 2013Natur.501...45J }}</ref>
-The definition of a prion-like domain arises from the study of fungal prions. In yeast, prionogenic proteins have a portable prion domain that is both necessary and sufficient for self-templating and protein aggregation. This has been shown by attaching the prion domain to a reporter protein, which then aggregates like a known prion. Similarly, removing the prion domain from a fungal prion protein inhibits prionogenesis. This modular view of prion behaviour has led to the hypothesis that similar prion domains are present in animal proteins, in addition to PrP.<ref name="King 2012"/> These fungal prion domains have several characteristic sequence features. They are typically enriched in asparagine, glutamine, tyrosine and glycine residues, with an asparagine bias being particularly conducive to the aggregative property of prions. Historically, prionogenesis has been seen as independent of sequence and only dependent on relative residue content. However, this has been shown to be false, with the spacing of prolines and charged residues having been shown to be critical in amyloid formation.<ref name="Alberti, 2009">{{cite journal | vauthors = Alberti S, Halfmann R, King O, Kapila A, Lindquist S | title = A systematic survey identifies prions and illuminates sequence features of prionogenic proteins | journal = Cell | volume = 137 | issue = 1 | pages = 146–58 | year = 2009 | pmid = 19345193 | pmc = 2683788 | doi = 10.1016/j.cell.2009.02.044 }}</ref>
+The definition of a prion-like domain arises from the study of fungal prions. In yeast, prionogenic proteins have a portable prion domain that is both necessary and sufficient for self-templating and protein aggregation. This has been shown by attaching the prion domain to a reporter protein, which then aggregates like a known prion. Similarly, removing the prion domain from a fungal prion protein inhibits prionogenesis. This modular view of prion behaviour has led to the hypothesis that similar prion domains are present in animal proteins, in addition to PrP.<ref name="King 2012"/> These fungal prion domains have several characteristic sequence features. They are typically enriched in asparagine, glutamine, tyrosine and glycine residues, with an asparagine bias being particularly conducive to the aggregative property of prions. Historically, prionogenesis has been seen as independent of sequence and only dependent on relative residue content. However, this has been shown to be false, with the spacing of prolines and charged residues having been shown to be critical in amyloid formation.<ref name="Alberti, 2009">{{cite journal | vauthors = Alberti S, Halfmann R, King O, Kapila A, Lindquist S | title = A systematic survey identifies prions and illuminates sequence features of prionogenic proteins | journal = Cell | volume = 137 | issue = 1 | pages = 146–158 | date = April 2009 | pmid = 19345193 | pmc = 2683788 | doi = 10.1016/j.cell.2009.02.044 }}</ref>
 Bioinformatic screens have predicted that over 250 human proteins contain prion-like domains (PrLD). These domains are hypothesized to have the same transmissible, amyloidogenic properties of PrP and known fungal proteins. As in yeast, proteins involved in gene expression and RNA binding seem to be particularly enriched in PrLD's, compared to other classes of protein. In particular, 29 of the known 210 proteins with an RNA recognition motif also have a putative prion domain. Meanwhile, several of these RNA-binding proteins have been independently identified as pathogenic in cases of ALS, FTLD-U, Alzheimer's disease, and Huntington's disease.<ref name="Eisenberg2012"/>
 === Role in neurodegenerative disease ===
-The pathogenicity of prions and proteins with prion-like domains is hypothesized to arise from their self-templating ability and the resulting exponential growth of amyloid fibrils. The presence of [[amyloid]] fibrils in patients with degenerative diseases has been well documented. These amyloid fibrils are seen as the result of pathogenic proteins that self-propagate and form highly stable, non-functional aggregates.<ref name="Eisenberg2012">{{cite journal | vauthors = Eisenberg D, [[Mathias Jucker (neuroscientist)|Jucker M]] | title = The amyloid state of proteins in human diseases | journal = Cell | volume = 148 | issue = 6 | pages = 1188–203 | date = March 2012 | pmid = 22424229 | pmc = 3353745 | doi = 10.1016/j.cell.2012.02.022 }}</ref> While this does not necessarily imply a causal relationship between amyloid and degenerative diseases, the toxicity of certain amyloid forms and the overproduction of amyloid in familial cases of degenerative disorders supports the idea that amyloid formation is generally toxic.<ref>{{cite journal | vauthors = Ayers JI, Prusiner SB | title = Prion protein - mediator of toxicity in multiple proteinopathies | journal = Nature Reviews. Neurology | volume = 16 | issue = 4 | pages = 187–188 | date = April 2020 | pmid = 32123368 | doi = 10.1038/s41582-020-0332-8 | s2cid = 211728879 }}</ref>
+The pathogenicity of prions and proteins with prion-like domains is hypothesized to arise from their self-templating ability and the resulting exponential growth of amyloid fibrils. The presence of [[amyloid]] fibrils in patients with degenerative diseases has been well documented. These amyloid fibrils are seen as the result of pathogenic proteins that self-propagate and form highly stable, non-functional aggregates.<ref name="Eisenberg2012">{{cite journal | vauthors = Eisenberg D, Jucker M | title = The amyloid state of proteins in human diseases | journal = Cell | volume = 148 | issue = 6 | pages = 1188–1203 | date = March 2012 | pmid = 22424229 | pmc = 3353745 | doi = 10.1016/j.cell.2012.02.022 }}</ref> While this does not necessarily imply a causal relationship between amyloid and degenerative diseases, the toxicity of certain amyloid forms and the overproduction of amyloid in familial cases of degenerative disorders supports the idea that amyloid formation is generally toxic.<ref>{{cite journal | vauthors = Ayers JI, Prusiner SB | title = Prion protein - mediator of toxicity in multiple proteinopathies | journal = Nature Reviews. Neurology | volume = 16 | issue = 4 | pages = 187–188 | date = April 2020 | pmid = 32123368 | doi = 10.1038/s41582-020-0332-8 | s2cid = 211728879 }}</ref>
 Specifically, aggregation of [[TARDBP|TDP-43]], an RNA-binding protein, has been found in ALS/MND patients, and mutations in the genes coding for these proteins have been identified in familial cases of ALS/MND. These mutations promote the misfolding of the proteins into a prion-like conformation. The misfolded form of TDP-43 forms cytoplasmic inclusions in affected neurons, and is found depleted in the nucleus. In addition to ALS/MND and FTLD-U, TDP-43 pathology is a feature of many cases of Alzheimer's disease, Parkinson's disease and Huntington's disease. The misfolding of TDP-43 is largely directed by its prion-like domain. This domain is inherently prone to misfolding, while pathological mutations in TDP-43 have been found to increase this propensity to misfold, explaining the presence of these mutations in familial cases of ALS/MND. As in yeast, the prion-like domain of TDP-43 has been shown to be both necessary and sufficient for protein misfolding and aggregation.<ref name="King 2012"/>
-Similarly, pathogenic mutations have been identified in the prion-like domains of heterogeneous nuclear riboproteins hnRNPA2B1 and hnRNPA1 in familial cases of muscle, brain, bone and motor neuron degeneration. The wild-type form of all of these proteins show a tendency to self-assemble into amyloid fibrils, while the pathogenic mutations exacerbate this behaviour and lead to excess accumulation.<ref name="Kim 2013">{{cite journal | vauthors = Kim HJ, Kim NC, Wang YD, Scarborough EA, Moore J, Diaz Z, MacLea KS, Freibaum B, Li S, Molliex A, Kanagaraj AP, Carter R, Boylan KB, Wojtas AM, Rademakers R, Pinkus JL, Greenberg SA, Trojanowski JQ, Traynor BJ, Smith BN, Topp S, Gkazi AS, Miller J, Shaw CE, Kottlors M, Kirschner J, Pestronk A, Li YR, Ford AF, Gitler AD, Benatar M, King OD, Kimonis VE, Ross ED, Weihl CC, Shorter J, Taylor JP | title = Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS | journal = Nature | volume = 495 | issue = 7442 | pages = 467–73 | date = March 2013 | pmid = 23455423 | pmc = 3756911 | doi = 10.1038/nature11922 | bibcode = 2013Natur.495..467K }}</ref>
+Similarly, pathogenic mutations have been identified in the prion-like domains of heterogeneous nuclear riboproteins hnRNPA2B1 and hnRNPA1 in familial cases of muscle, brain, bone and motor neuron degeneration. The wild-type form of all of these proteins show a tendency to self-assemble into amyloid fibrils, while the pathogenic mutations exacerbate this behaviour and lead to excess accumulation.<ref name="Kim 2013">{{cite journal | vauthors = Kim HJ, Kim NC, Wang YD, Scarborough EA, Moore J, Diaz Z, MacLea KS, Freibaum B, Li S, Molliex A, Kanagaraj AP, Carter R, Boylan KB, Wojtas AM, Rademakers R, Pinkus JL, Greenberg SA, Trojanowski JQ, Traynor BJ, Smith BN, Topp S, Gkazi AS, Miller J, Shaw CE, Kottlors M, Kirschner J, Pestronk A, Li YR, Ford AF, Gitler AD, Benatar M, King OD, Kimonis VE, Ross ED, Weihl CC, Shorter J, Taylor JP | title = Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS | journal = Nature | volume = 495 | issue = 7442 | pages = 467–473 | date = March 2013 | pmid = 23455423 | pmc = 3756911 | doi = 10.1038/nature11922 | bibcode = 2013Natur.495..467K }}</ref>
 == Weaponization ==
@@ Line 266: / Line 266: @@
 == History ==
-In the 18th and 19th centuries, exportation of sheep from Spain was observed to coincide with a disease called [[scrapie]]. This disease caused the affected animals to ''"lie down, bite at their feet and legs, rub their backs against posts, fail to thrive, stop feeding and finally become lame"''.<ref>{{Cite web|title=How Prions Came to Be: A Brief History – Infectious Disease: Superbugs, Science, & Society|url=https://sites.duke.edu/superbugs/module-6/prions-mad-cow-disease-when-proteins-go-bad/how-prions-came-to-be-a-brief-history/|access-date=2021-09-17|language=en-US|archive-date=2021-09-17|archive-url=https://web.archive.org/web/20210917234712/https://sites.duke.edu/superbugs/module-6/prions-mad-cow-disease-when-proteins-go-bad/how-prions-came-to-be-a-brief-history/|url-status=live}}</ref> The disease was also observed to have the long incubation period that is a key characteristic of [[Transmissible spongiform encephalopathy|transmissible spongiform encephalopathies (TSEs)]]. Although the cause of scrapie was not known back then, it is probably the first transmissible spongiform encephalopathy to be recorded.<ref>{{Cite journal |last1=Ness |first1=Anthony |last2=Aiken |first2=Judd |last3=McKenzie |first3=Debbie |date=2023-12-31 |title=Sheep scrapie and deer rabies in England prior to 1800 |journal=Prion |language=en |volume=17 |issue=1 |pages=7–15 |doi=10.1080/19336896.2023.2166749 |issn=1933-6896 |pmc=9858414 |pmid=36654484}}</ref>
+In the 18th and 19th centuries, exportation of sheep from Spain was observed to coincide with a disease called [[scrapie]]. This disease caused the affected animals to ''"lie down, bite at their feet and legs, rub their backs against posts, fail to thrive, stop feeding and finally become lame"''.<ref>{{Cite web|title=How Prions Came to Be: A Brief History – Infectious Disease: Superbugs, Science, & Society|url=https://sites.duke.edu/superbugs/module-6/prions-mad-cow-disease-when-proteins-go-bad/how-prions-came-to-be-a-brief-history/|access-date=2021-09-17|language=en-US|archive-date=2021-09-17|archive-url=https://web.archive.org/web/20210917234712/https://sites.duke.edu/superbugs/module-6/prions-mad-cow-disease-when-proteins-go-bad/how-prions-came-to-be-a-brief-history/|url-status=live}}</ref> The disease was also observed to have the long incubation period that is a key characteristic of [[Transmissible spongiform encephalopathy|transmissible spongiform encephalopathies (TSEs)]]. Although the cause of scrapie was not known back then, it is probably the first transmissible spongiform encephalopathy to be recorded.<ref>{{cite journal | vauthors = Ness A, Aiken J, McKenzie D | title = Sheep scrapie and deer rabies in England prior to 1800 | journal = Prion | volume = 17 | issue = 1 | pages = 7–15 | date = December 2023 | pmid = 36654484 | pmc = 9858414 | doi = 10.1080/19336896.2023.2166749 }}</ref>
-In the 1950s, [[Daniel Carleton Gajdusek|Carleton Gajdusek]] began research which eventually showed that [[Kuru (disease)|kuru]] could be transmitted to chimpanzees by what was possibly a new infectious agent, work for which he eventually won the 1976 [[Nobel prize]]. During the 1960s, two London-based researchers, radiation biologist [[Tikvah Alper]] and biophysicist [[John Stanley Griffith]], developed the hypothesis that the [[transmissible spongiform encephalopathy|transmissible spongiform encephalopathies]] are caused by an infectious agent consisting solely of proteins.<ref>{{cite journal | vauthors = Alper T, Cramp WA, Haig DA, Clarke MC | s2cid = 4195902 | title = Does the agent of scrapie replicate without nucleic acid? | journal = Nature | volume = 214 | issue = 5090 | pages = 764–66 | date = May 1967 | pmid = 4963878 | doi = 10.1038/214764a0 | bibcode = 1967Natur.214..764A }}</ref><ref>{{cite journal | vauthors = Griffith JS | s2cid = 4171947 | title = Self-replication and scrapie | journal = Nature | volume = 215 | issue = 5105 | pages = 1043–44 | date = September 1967 | pmid = 4964084 | doi = 10.1038/2151043a0 | bibcode = 1967Natur.215.1043G }}</ref> Earlier investigations by [[E.J. Field]] into [[scrapie]] and kuru had found evidence for the transfer of pathologically inert polysaccharides that only become infectious post-transfer, in the new host.<ref name="pmid5950508">{{cite journal | vauthors = Field EJ | title = Transmission experiments with multiple sclerosis: an interim report | journal = British Medical Journal | volume = 2 | issue = 5513 | pages = 564–65 | date = September 1966 | pmid = 5950508 | pmc = 1943767 | doi = 10.1136/bmj.2.5513.564 }}</ref><ref name="pmid4175093">{{cite journal | vauthors = Adams DH, Field EJ | title = The infective process in scrapie | journal = Lancet | volume = 2 | issue = 7570 | pages = 714–16 | date = September 1968 | pmid = 4175093 | doi = 10.1016/s0140-6736(68)90754-x }}</ref> Alper and Griffith wanted to account for the discovery that the mysterious infectious agent causing the diseases scrapie and [[Creutzfeldt–Jakob disease]] resisted [[ionizing radiation]].<ref>{{cite journal | vauthors = Field EJ, Farmer F, Caspary EA, Joyce G | s2cid = 4195610 | title = Susceptibility of scrapie agent to ionizing radiation | journal = Nature | volume = 222 | issue = 5188 | pages = 90–91 | date = April 1969 | pmid = 4975649 | doi = 10.1038/222090a0 | series = 5188 | bibcode = 1969Natur.222...90F }}</ref> Griffith proposed three ways in which a protein could be a [[pathogen]].<ref>{{cite journal | vauthors = Griffith JS | s2cid = 4171947 | title = Self-replication and scrapie | journal = Nature | volume = 215 | issue = 5105 | pages = 1043–44| date = Sep 1967 | pmid = 4964084 | doi = 10.1038/2151043a0 | bibcode = 1967Natur.215.1043G }}</ref>
+In the 1950s, [[Daniel Carleton Gajdusek|Carleton Gajdusek]] began research which eventually showed that [[Kuru (disease)|kuru]] could be transmitted to chimpanzees by what was possibly a new infectious agent, work for which he eventually won the 1976 [[Nobel prize]]. During the 1960s, two London-based researchers, radiation biologist [[Tikvah Alper]] and biophysicist [[John Stanley Griffith]], developed the hypothesis that the [[transmissible spongiform encephalopathy|transmissible spongiform encephalopathies]] are caused by an infectious agent consisting solely of proteins.<ref>{{cite journal | vauthors = Alper T, Cramp WA, Haig DA, Clarke MC | title = Does the agent of scrapie replicate without nucleic acid? | journal = Nature | volume = 214 | issue = 5090 | pages = 764–766 | date = May 1967 | pmid = 4963878 | doi = 10.1038/214764a0 | s2cid = 4195902 | bibcode = 1967Natur.214..764A }}</ref><ref>{{cite journal | vauthors = Griffith JS | title = Self-replication and scrapie | journal = Nature | volume = 215 | issue = 5105 | pages = 1043–1044 | date = September 1967 | pmid = 4964084 | doi = 10.1038/2151043a0 | s2cid = 4171947 | bibcode = 1967Natur.215.1043G }}</ref> Earlier investigations by [[E.J. Field]] into [[scrapie]] and kuru had found evidence for the transfer of pathologically inert polysaccharides that only become infectious post-transfer, in the new host.<ref name="pmid5950508">{{cite journal | vauthors = Field EJ | title = Transmission experiments with multiple sclerosis: an interim report | journal = British Medical Journal | volume = 2 | issue = 5513 | pages = 564–565 | date = September 1966 | pmid = 5950508 | pmc = 1943767 | doi = 10.1136/bmj.2.5513.564 }}</ref><ref name="pmid4175093">{{cite journal | vauthors = Adams DH, Field EJ | title = The infective process in scrapie | journal = Lancet | volume = 2 | issue = 7570 | pages = 714–716 | date = September 1968 | pmid = 4175093 | doi = 10.1016/s0140-6736(68)90754-x }}</ref> Alper and Griffith wanted to account for the discovery that the mysterious infectious agent causing the diseases scrapie and [[Creutzfeldt–Jakob disease]] resisted [[ionizing radiation]].<ref>{{cite journal | vauthors = Field EJ, Farmer F, Caspary EA, Joyce G | title = Susceptibility of scrapie agent to ionizing radiation | journal = Nature | volume = 222 | issue = 5188 | pages = 90–91 | date = April 1969 | pmid = 4975649 | doi = 10.1038/222090a0 | series = 5188 | s2cid = 4195610 | bibcode = 1969Natur.222...90F }}</ref> Griffith proposed three ways in which a protein could be a [[pathogen]].<ref>{{cite journal | vauthors = Griffith JS | title = Self-replication and scrapie | journal = Nature | volume = 215 | issue = 5105 | pages = 1043–1044 | date = September 1967 | pmid = 4964084 | doi = 10.1038/2151043a0 | s2cid = 4171947 | bibcode = 1967Natur.215.1043G }}</ref>
 In the first [[hypothesis]], he suggested that if the protein is the product of a normally suppressed [[gene]], and introducing the protein could induce the gene's expression, that is, wake the dormant gene up, then the result would be a process indistinguishable from replication, as the gene's expression would produce the protein, which would then wake the gene in other [[cell (biology)|cells]].{{citation needed|date=January 2023}}
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 His third hypothesis proposed that the agent could be an [[antibody]] if the antibody was its own target [[antigen]], as such an antibody would result in more and more antibody being produced against itself. However, Griffith acknowledged that this third hypothesis was unlikely to be true due to the lack of a detectable [[immune response]].<ref name="researchgate.net">{{cite book | vauthors = Bolton D | chapter-url = https://www.researchgate.net/publication/235220355 | chapter = Prions, the Protein Hypothesis, and Scientific Revolutions | veditors = Nunnally BK, Krull IS | title = Prions and Mad Cow Disease | publisher = Marcel Dekker | date = January 1, 2004 | pages = 21–60 | via = ResearchGate | isbn = 978-0-203-91297-3 | access-date = July 27, 2018 | archive-date = March 22, 2022 | archive-url = https://web.archive.org/web/20220322123428/https://www.researchgate.net/publication/235220355_Prions_the_Protein_Hypothesis_and_Scientific_Revolutions | url-status = live }}</ref>
-[[Francis Crick]] recognized the potential significance of the Griffith protein-only hypothesis for scrapie propagation in the second edition of his "[[Central dogma of molecular biology]]" (1970): While asserting that the flow of sequence information from protein to protein, or from protein to RNA and DNA was "precluded", he noted that Griffith's hypothesis was a potential contradiction (although it was not so promoted by Griffith).<ref>{{cite journal | vauthors = Crick F | s2cid = 4164029 | title = Central dogma of molecular biology | journal = Nature | volume = 227 | issue = 5258 | pages = 561–63 | date = August 1970 | pmid = 4913914 | doi = 10.1038/227561a0 | bibcode = 1970Natur.227..561C }}</ref> The revised hypothesis was later formulated, in part, to accommodate [[reverse transcription]] (which both [[Howard Martin Temin|Howard Temin]] and [[David Baltimore]] discovered in 1970).<ref name="pmid27482900">{{cite journal |vauthors=Coffin JM, Fan H |title=The Discovery of Reverse Transcriptase |journal=Annual Review of Virology |volume=3 |issue=1 |pages=29–51 |date=September 2016 |pmid=27482900 |doi=10.1146/annurev-virology-110615-035556 |doi-access=free }}</ref>
+[[Francis Crick]] recognized the potential significance of the Griffith protein-only hypothesis for scrapie propagation in the second edition of his "[[Central dogma of molecular biology]]" (1970): While asserting that the flow of sequence information from protein to protein, or from protein to RNA and DNA was "precluded", he noted that Griffith's hypothesis was a potential contradiction (although it was not so promoted by Griffith).<ref>{{cite journal | vauthors = Crick F | title = Central dogma of molecular biology | journal = Nature | volume = 227 | issue = 5258 | pages = 561–563 | date = August 1970 | pmid = 4913914 | doi = 10.1038/227561a0 | s2cid = 4164029 | bibcode = 1970Natur.227..561C }}</ref> The revised hypothesis was later formulated, in part, to accommodate [[reverse transcription]] (which both [[Howard Martin Temin|Howard Temin]] and [[David Baltimore]] discovered in 1970).<ref name="pmid27482900">{{cite journal | vauthors = Coffin JM, Fan H | title = The Discovery of Reverse Transcriptase | journal = Annual Review of Virology | volume = 3 | issue = 1 | pages = 29–51 | date = September 2016 | pmid = 27482900 | doi = 10.1146/annurev-virology-110615-035556 | doi-access = free }}</ref>
-In 1982, [[Stanley B. Prusiner]] of the [[University of California, San Francisco]], announced that his team had purified the hypothetical infectious protein, which did not appear to be present in healthy hosts, though they did not manage to isolate the protein until two years after Prusiner's announcement.<ref>{{cite journal | vauthors = Taubes G | author-link = Gary Taubes | title =The game of name is fame. But is it science? |journal=Discover |volume=7 |issue=12 |pages= 28–41 |date=December 1986 }}</ref><ref name="Prusiner82">{{cite journal | vauthors = Prusiner SB | s2cid = 7447120 | title = Novel proteinaceous infectious particles cause scrapie | journal = Science | volume = 216 | issue = 4542 | pages = 136–44 | date = April 1982 | pmid = 6801762 | doi = 10.1126/science.6801762 | bibcode = 1982Sci...216..136P | url = https://pdfs.semanticscholar.org/f292/b22e2675419c6392a5e55f6b35b1dfc46917.pdf | archive-url = https://web.archive.org/web/20200720113942/https://pdfs.semanticscholar.org/f292/b22e2675419c6392a5e55f6b35b1dfc46917.pdf | url-status = dead | archive-date = 2020-07-20 }}</ref> The protein was named a prion, for "proteinacious infectious particle", derived from the words '''pr'''otein and infect'''ion'''. When the prion was discovered, Griffith's first hypothesis, that the protein was the product of a normally silent gene was favored by many. It was subsequently discovered, however, that the same protein exists in normal hosts but in different form.<ref name="pmid26645475">{{cite journal |vauthors=Atkinson CJ, Zhang K, Munn AL, Wiegmans A, Wei MQ |title=Prion protein scrapie and the normal cellular prion protein |journal=Prion |volume=10 |issue=1 |pages=63–82 |date=2016 |pmid=26645475 |pmc=4981215 |doi=10.1080/19336896.2015.1110293 }}</ref>
+In 1982, [[Stanley B. Prusiner]] of the [[University of California, San Francisco]], announced that his team had purified the hypothetical infectious protein, which did not appear to be present in healthy hosts, though they did not manage to isolate the protein until two years after Prusiner's announcement.<ref>{{cite journal | vauthors = Taubes G | author-link = Gary Taubes | title =The game of name is fame. But is it science? |journal=Discover |volume=7 |issue=12 |pages= 28–41 |date=December 1986 }}</ref><ref name="Prusiner82">{{cite journal | vauthors = Prusiner SB | title = Novel proteinaceous infectious particles cause scrapie | journal = Science | volume = 216 | issue = 4542 | pages = 136–144 | date = April 1982 | pmid = 6801762 | doi = 10.1126/science.6801762 | url = https://pdfs.semanticscholar.org/f292/b22e2675419c6392a5e55f6b35b1dfc46917.pdf | url-status = dead | s2cid = 7447120 | bibcode = 1982Sci...216..136P | archive-url = https://web.archive.org/web/20200720113942/https://pdfs.semanticscholar.org/f292/b22e2675419c6392a5e55f6b35b1dfc46917.pdf | archive-date = 2020-07-20 }}</ref> The protein was named a prion, for "proteinacious infectious particle", derived from the words '''pr'''otein and infect'''ion'''. When the prion was discovered, Griffith's first hypothesis, that the protein was the product of a normally silent gene was favored by many. It was subsequently discovered, however, that the same protein exists in normal hosts but in different form.<ref name="pmid26645475">{{cite journal | vauthors = Atkinson CJ, Zhang K, Munn AL, Wiegmans A, Wei MQ | title = Prion protein scrapie and the normal cellular prion protein | journal = Prion | volume = 10 | issue = 1 | pages = 63–82 | date = 2016 | pmid = 26645475 | pmc = 4981215 | doi = 10.1080/19336896.2015.1110293 }}</ref>
 Following the discovery of the same protein in different form in uninfected individuals, the specific protein that the prion was composed of was named the prion protein (PrP), and Griffith's second hypothesis that an abnormal form of a host protein can convert other proteins of the same type into its abnormal form, became the dominant theory.<ref name="researchgate.net"/> Prusiner was awarded the [[Nobel Prize in Physiology or Medicine]] in 1997 for his research into prions.<ref name="nobel">{{cite web | url = http://nobelprize.org/nobel_prizes/medicine/laureates/1997/ | title = The Nobel Prize in Physiology or Medicine, 1997 | access-date = 2010-02-28 | publisher = NobelPrize.org | quote = The Nobel Prize in Physiology or Medicine 1997 was awarded to Stanley B. Prusiner 'for his discovery of Prions - a new biological principle of infection.' | archive-date = 2018-08-09 | archive-url = https://web.archive.org/web/20180809231715/https://www.nobelprize.org/nobel_prizes/medicine/laureates/1997/ | url-status = live }}</ref><ref>{{Cite web| vauthors = Frazer J |title=Prions Are Forever|url=https://blogs.scientificamerican.com/artful-amoeba/prions-are-forever/|access-date=2021-12-28|website=Scientific American Blog Network|language=en|archive-date=2022-01-04|archive-url=https://web.archive.org/web/20220104103748/https://blogs.scientificamerican.com/artful-amoeba/prions-are-forever/|url-status=live}}</ref>