Parkinson

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Background

Data suggest that cholesterol metabolism is linked to susceptibility to Alzheimer’s disease.


However, no direct evidence was reported linking cholesterol metabolism and Alzheimer
disease. To demonstrate the relation between 𝜷 amyloid peptides deposition can be modulated
by high cholesterol diet, mouse were used to examine the accumulation of 𝜷 amyloid peptides
in the central nervous system [1].
The experiment done by Reolfo and Pappolla showed that a high cholesterol diet increases
the level of cholesterol in plasma and central nervous system, resulting in an increased load
and deposit of 𝜷 amyloid peptides [1]. This implies that dietary methods might offer a path to
prevention of AD without resorting to drugs that are expensive and may have harmful side
effects [1].
1. Protein kinase C delta type Calcium-independent, phospholipid- and diacylglycerol
(DAG)-dependent serine/threonine-protein kinase that plays contrasting roles in cell
death and cell survival by functioning as a pro-apoptotic protein during DNA
damage-induced apoptosis, but acting as an anti-apoptotic protein during cytokine
receptor-initiated cell death, is involved in tumor suppression, is required for oxygen
radical production by NADPH oxidase and acts as positive or negative regulator in
platelet functional responses. Negatively regulates B cell proliferation and also has an
important function in self-antigen induced B cell tolerance induction. Upon DNA
damage, activates the promoter of the death-promoting transcription factor
BCLAF1/Btf to trigger BCLAF1-mediated p53/TP53 gene transcription and
apoptosis. In response to oxidative stress, interact with and activate CHUK/IKKA in
the nucleus, causing the phosphorylation of p53/TP53. In the case of ER stress or
DNA damage-induced apoptosis, can form a complex with the tyrosine-protein kinase
ABL1 which trigger apoptosis independently of p53/TP53. In cytosol can trigger
apoptosis by activating MAPK11 or MAPK14, inhibiting AKT1 and decreasing the
level of X-linked inhibitor of apoptosis protein (XIAP), whereas in nucleus induces
apoptosis via the activation of MAPK8 or MAPK9. Upon ionizing radiation
treatment, is required for the activation of the apoptosis regulators BAX and BAK,
which trigger the mitochondrial cell death pathway. Can phosphorylate MCL1 and
target it for degradation which is sufficient to trigger for BAX activation and
apoptosis. Is required for the control of cell cycle progression both at G1/S and G2/M
phases. Mediates phorbol 12-myristate 13-acetate (PMA)-induced inhibition of cell
cycle progression at G1/S phase by up-regulating the CDK inhibitor CDKN1A/p21
and inhibiting the cyclin CCNA2 promoter activity. In response to UV irradiation can
phosphorylate CDK1, which is important for the G2/M DNA damage checkpoint
activation. Can protect glioma cells from the apoptosis induced by TNFSF10/TRAIL,
probably by inducing increased phosphorylation and subsequent activation of AKT1.
Can also act as tumor suppressor upon mitogenic stimulation with PMA or TPA. In
N-formyl-methionyl-leucyl-phenylalanine (fMLP)-treated cells, is required for NCF1
(p47-phox) phosphorylation and activation of NADPH oxidase activity, and regulates
TNF-elicited superoxide anion production in neutrophils, by direct phosphorylation
and activation of NCF1 or indirectly through MAPK1/3 (ERK1/2) signaling
pathways. May also play a role in the regulation of NADPH oxidase activity in
eosinophil after stimulation with IL5, leukotriene B4 or PMA. In collagen-induced
platelet aggregation, acts a negative regulator of filopodia formation and actin
polymerization by interacting with and negatively regulating VASP phosphorylation.
Downstream of PAR1, PAR4 and CD36/GP4 receptors, regulates differentially
platelet dense granule secretion; acts as a positive regulator in PAR-mediated granule
secretion, whereas it negatively regulates CD36/GP4-mediated granule release.
Phosphorylates MUC1 in the C-terminal and regulates the interaction between MUC1
and beta-catenin. The catalytic subunit phosphorylates 14-3-3 proteins (YWHAB,
YWHAZ and YWHAH) in a sphingosine-dependent fashion. Phosphorylates
ELAVL1 in response to angiotensin-2 treatment.
Catalytic activity
ATP + a protein = ADP + a phosphoprotein.
ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.
Enzyme Activity
Novel PKCs (PRKCD, PRKCE, PRKCH and PRKCQ) are calcium-insensitive, but activated
by diacylglycerol (DAG) and phosphatidylserine. Three specific sites; Thr-505 (activation
loop of the kinase domain), Ser-643 (turn motif) and Ser-662 (hydrophobic region), need to
be phosphorylated for its full activation. Activated by caspase-3 (CASP3) cleavage during
apoptosis. After cleavage, the pseudosubstrate motif in the regulatory subunit is released from
the substrate recognition site of the catalytic subunit, which enables PRKCD to become
constitutively activated. The catalytic subunit which displays properties of a
sphingosine-dependent protein kinase is activated by D-erythro-sphingosine (Sph) or
N,N-dimethyl-D-erythrosphingosine (DMS) or N,N,N-trimethyl-D-erythrosphingosine
(TMS), but not by ceramide or Sph-1-P and is strongly inhibited by phosphatidylserine
Protein kinase C delta type Subcellular Location

2. Amyloid beta A4 protein

Function
Functions as a cell surface receptor and performs physiological functions on the surface of
neurons relevant to neurite growth, neuronal adhesion and axonogenesis. Involved in cell
mobility and transcription regulation through protein-protein interactions. Can promote
transcription activation through binding to APBB1-KAT5 and inhibit Notch signaling
through interaction with Numb. Couples to apoptosis-inducing pathways such as those
mediated by G(O) and JIP. Inhibits G(o) alpha ATPase activity (By similarity). Acts as a
kinesin I membrane receptor, mediating the axonal transport of beta-secretase and presenilin
1. May be involved in copper homeostasis/oxidative stress through copper ion reduction. Can
regulate neurite outgrowth through binding to components of the extracellular matrix such as
heparin and collagen I and IV (By similarity). The splice isoforms that contain the BPTI
domain possess protease inhibitor activity. Induces a AGER-dependent pathway that involves
activation of p38 MAPK, resulting in internalization of amyloid-beta peptide and leading to
mitochondrial dysfunction in cultured cortical neurons (By similarity). Provides Cu2+ ions for
GPC1 which are required for release of nitric oxide (NO) and subsequent degradation of the
heparan sulfate chains on GPC1.
Amyloid-beta peptides are lipophilic metal chelators with metal-reducing activity. Binds
transient metals such as copper, zinc and iron. Rat and mouse amyloid-beta peptides bind
only weakly transient metals and have little reducing activity due to substitutions of transient
metal chelating residues. Amyloid-beta protein 42 may activate mononuclear phagocytes in
the brain and elicit inflammatory responses. Promotes both tau aggregation and TPK
II-mediated phosphorylation. Also binds GPC1 in lipid rafts.
The gamma-CTF peptides as well as the caspase-cleaved peptides, including C31, are potent
enhancers of neuronal apoptosis.
N-APP binds TNFRSF21 triggering caspase activation and degeneration of both neuronal cell
bodies (via caspase-3) and axons (via caspase-6).

Miscellaneous

Chelation of metal ions, notably copper, iron and zinc, can induce histidine-bridging between
amyloid-beta molecules resulting in amyloid-beta-metal aggregates. Rat and mouse
amyloid-beta peptides have an arginine residue substituted for the bridging histidine residue
and are thus less capable of forming amyloid aggregates. Extracellular zinc-binding increases
binding of heparin to APP and inhibits collagen-binding (By similarity).
Amyloid beta A4 protein Subcellular Location

3. Disintegrin and metalloproteinase domain-containing protein 9


Cleaves and releases a number of molecules with important roles in tumorigenesis and
angiogenesis, such as TEK, KDR, EPHB4, CD40, VCAM1 and CDH5 (PubMed:19273593).
May mediate cell-cell, cell-matrix interactions and regulate the motility of cells via interactio
Cofactor
Zn2+
Enzyme regulation
Synthesized as an inactive form which is proteolytically cleaved to generate an active
enzyme. Processing at the upstream site is particularly important for activation of the
proenzyme, whereas processing at the boundary between the pro-domain and the catalytic
domain does not appear to be essential (PubMed:25795784). Inhibited by hydroxamic
acid-based inhibitors (PubMed:9920899).
Disintegrin and metalloproteinase domain-containing protein 9 Subcellular
Location

4. Histone acetyltransferase KAT5


Función
Catalytic subunit of the NuA4 histone acetyltransferase complex which is involved in
transcriptional activation of select genes principally by acetylation of nucleosomal histones
H4 and H2A. This modification may both alter nucleosome - DNA interactions and promote
interaction of the modified histones with other proteins which positively regulate
transcription. This complex may be required for the activation of transcriptional programs
associated with oncogene and proto-oncogene mediated growth induction, tumor suppressor
mediated growth arrest and replicative senescence, apoptosis, and DNA repair. The NuA4
complex ATPase and helicase activities seem to be, at least in part, contributed by the
association of RUVBL1 and RUVBL2 with EP400. NuA4 may also play a direct role in
DNA repair when recruited to sites of DNA damage. Directly acetylates and activates ATM.
Relieves NR1D2-mediated inhibition of APOC3 expression by acetylating NR1D2.
Component of a SWR1-like complex that specifically mediates the removal of histone
H2A.Z/H2AFZ from the nucleosome. Promotes FOXP3 acetylation and positively regulates
its transcriptional repressor activity. Acetylates RAN at 'Lys-134'.
Actividad catalítica:
Acetyl-CoA + [protein]-L-lysine = CoA + [protein]-N6-acetyl-L-lysine.
Histone acetyltransferase KAT5 Subcellular Location

5. Kinesin light chain 1


Función
Kinesin is a microtubule-associated force-producing protein that may play a role in organelle
transport. The light chain may function in coupling of cargo to the heavy chain or in the
modulation of its ATPase activity.

Reference:
[1] Lorenzo M. Refolo, Miguel A. Pappolla et al.. (2000). Hypercholesterolemia Accelerates
the Alzheimer’s Amyloid Pathology in a Transgenic Mouse Model. 07/03/2018, from
ELSEVIER Website:
https://ac.els-cdn.com/S0969996100903048/1-s2.0-S0969996100903048-main.pdf?_tid=c35
2b9d3-ad8c-4561-89f5-0b5647189876&acdnat=1520464751_8653e7165c4ef760538428059
96e86cd
[2] Uniprot. 07/03/2018 from Website: http://www.uniprot.org/uniprot/P28867
[3] Uniprot. 07/03/2018 from Website: http://www.uniprot.org/uniprot/Q61072
[4] Uniprot. 07/03/2018 from Website: http://www.uniprot.org/uniprot/Q61072
[5] Uniprot. 07/03/2018 from Website: http://www.uniprot.org/uniprot/Q8CHK4
[6]Uniprot. 07/03/2018 from Website: http://www.uniprot.org/uniprot/O88447

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