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{{Short description|Protein-coding gene in the species Homo sapiens}}
{{Infobox_gene}}
{{Infobox_gene}}

'''Glial cell-derived neurotrophic factor''' ('''GDNF''') is a [[protein]] that, in humans, is encoded by the ''GDNF'' [[gene]].<ref name="pmid8493557">{{cite journal | vauthors = Lin LF, Doherty DH, Lile JD, Bektesh S, Collins F | title = GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons | journal = Science | volume = 260 | issue = 5111 | pages = 1130–2 | date = May 1993 | pmid = 8493557 | doi = 10.1126/science.8493557 | bibcode = 1993Sci...260.1130L }}</ref> GDNF is a small protein that potently promotes the survival of many types of [[neurons]].<ref name="entrez">{{cite web | title = Entrez Gene: GDNF glial cell derived neurotrophic factor| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2668}}</ref> It signals through [[GFRα|GFRα receptors]], particularly [[GFRα1]].
'''Glial cell line-derived neurotrophic factor''' ('''GDNF''') is a [[protein]] that, in humans, is encoded by the ''GDNF'' [[gene]].<ref name="pmid8493557">{{cite journal | vauthors = Lin LF, Doherty DH, Lile JD, Bektesh S, Collins F | title = GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons | journal = Science | volume = 260 | issue = 5111 | pages = 1130–2 | date = May 1993 | pmid = 8493557 | doi = 10.1126/science.8493557 | bibcode = 1993Sci...260.1130L }}</ref> GDNF is a small protein that potently promotes the survival of many types of [[neurons]].<ref name="entrez">{{cite web| title = Entrez Gene: GDNF glial cell derived neurotrophic factor| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2668| access-date = 2017-08-31| archive-date = 2010-03-07| archive-url = https://web.archive.org/web/20100307225046/http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2668| url-status = live}}</ref> It signals through [[GFRα|GFRα receptors]], particularly [[GFRα1]].
It is also responsible for the determination of spermatogonia into primary spermatocytes i.e. It is received by RET and by forming gradient with SCF it divides the spermatogonia into two cells.
As the result there is retention of spermatogonia and formation of spermatocyte. [Scott F. Gilbert]
It is also responsible for the determination of spermatogonia into primary spermatocytes, i.e. it is received by [[RET proto-oncogene]] (RET) and by forming gradient with SCF it divides the spermatogonia into two cells. As the result there is retention of spermatogonia and formation of spermatocyte.<ref>Scott F. Gilbert</ref>{{Full citation needed|date=November 2021}}


==GDNF family of ligands (GFL)==
==GDNF family of ligands (GFL)==
GDNF was discovered in 1991,<ref name="vastag">{{cite journal | vauthors = Vastag B | title = Biotechnology: Crossing the barrier | journal = Nature | volume = 466 | issue = 7309 | pages = 916–8 | date = Aug 2010 | pmid = 20725015 | doi = 10.1038/466916a | doi-access = free }}</ref> and is the first member of the [[GDNF family of ligands]] (GFL) found.
GDNF was discovered in 1991,<ref name="vastag">{{cite journal | vauthors = Vastag B | title = Biotechnology: Crossing the barrier | journal = Nature | volume = 466 | issue = 7309 | pages = 916–8 | date = August 2010 | pmid = 20725015 | doi = 10.1038/466916a | doi-access = free }}</ref> and is the first member of the [[GDNF family of ligands]] (GFL) found.


== Function ==
== Function ==
GDNF is highly distributed throughout both the peripheral and central nervous system. It can be secreted by [[astrocytes]], [[oligodendrocytes]], [[Schwann cells]], [[motor neurons]], and [[skeletal muscle]] during the development and growth of neurons and other peripheral cells.<ref>{{cite journal | pmid=32897420 |title=GDNF synthesis, signaling, and retrograde transport in motor neurons}}</ref>.
GDNF is highly distributed throughout both the peripheral and central nervous system. It can be secreted by [[astrocytes]], [[oligodendrocytes]], [[Schwann cells]], [[motor neurons]], and [[skeletal muscle]] during the development and growth of neurons and other peripheral cells.<ref name="paper1"/>


The GDNF gene encodes a highly conserved [[neurotrophic factor]]. The recombinant form of this protein was shown to promote the survival and differentiation of [[dopaminergic neuron]]s in culture, and was able to prevent [[apoptosis]] of motor neurons induced by [[axotomy]]. GDNF is synthesized as a 211 amino acid-long [[protein precursor]], pro-GDNF. <ref name="paper1">{{cite journal | pmid=32897420 | title = GDNF synthesis, signaling, and retrograde transport in motor neurons }}</ref> The pre-sequence leads the protein to the endoplasmic reticulum for secretion. While secretion takes place, the [[protein precursor]] folds via a sulfide-sulfide bond and dimerizes. The protein then is modified by [[N-linked glycosylation]] during packaging and preparation in the [[Golgi apparatus]]. Finally, the [[protein precursor]] undergoes [[proteolysis]] due to a proteolytic consensus sequence in its [[C-terminus]] end and is cleaved to 134 amino acids. <ref name="paper1"></ref> [[Protease]]s that play a role in the proteolysis of pro-GDNF into mature GDNF include [[furin]], PACE4, PC5A, PC5B, and PC7. Because multiple proteases can cleave the protein precursor, four different mature forms of GDNF can be produced. <ref name="paper1"></ref> The proteolytic processing of GDNF requires SorLA, a protein sorting receptor. SorLA does not bind to any other GFLs. <ref name="paper2">{{cite journal | pmid=23333276 |title=SorLA controls neurotrophic activity by sorting of GDNF and its receptors GFRα1 and RET}}</ref> The mature form of the protein is a ligand for the product of the [[RET proto-oncogene|RET]] (rearranged during transfection) protooncogene. In addition to the transcript encoding GDNF, two additional alternative transcripts encoding distinct proteins, referred to as astrocyte-derived trophic factors, have also been described. Mutations in this gene may be associated with [[Hirschprung's disease|Hirschsprung's disease]].<ref name="entrez"/>
The GDNF gene encodes a highly conserved [[neurotrophic factor]]. The recombinant form of this protein was shown to promote the survival and differentiation of [[dopaminergic neuron]]s in culture, and was able to prevent [[apoptosis]] of motor neurons induced by [[axotomy]]. GDNF is synthesized as a 211 amino acid-long [[protein precursor]], pro-GDNF.<ref name="paper1">{{cite journal | vauthors = Cintrón-Colón AF, Almeida-Alves G, Boynton AM, Spitsbergen JM | title = GDNF synthesis, signaling, and retrograde transport in motor neurons | journal = Cell and Tissue Research | volume = 382 | issue = 1 | pages = 47–56 | date = October 2020 | pmid = 32897420 | doi = 10.1007/s00441-020-03287-6 | pmc = 7529617 | doi-access = free }}</ref> The pre-sequence leads the protein to the endoplasmic reticulum for secretion. While secretion takes place, the protein precursor folds via a sulfide-sulfide bond and dimerizes. The protein then is modified by [[N-linked glycosylation]] during packaging and preparation in the [[Golgi apparatus]]. Finally, the [[protein precursor]] undergoes [[proteolysis]] due to a proteolytic consensus sequence in its [[C-terminus]] end and is cleaved to 134 amino acids.<ref name="paper1" /> [[Protease]]s that play a role in the proteolysis of pro-GDNF into mature GDNF include [[furin]], PACE4, PC5A, PC5B, and PC7. Because multiple proteases can cleave the protein precursor, four different mature forms of GDNF can be produced.<ref name="paper1" /> The proteolytic processing of GDNF requires SorLA, a protein sorting receptor. SorLA does not bind to any other GFLs.<ref name="paper2">{{cite journal | vauthors = Glerup S, Lume M, Olsen D, Nyengaard JR, Vaegter CB, Gustafsen C, Christensen EI, Kjolby M, Hay-Schmidt A, Bender D, Madsen P, Saarma M, Nykjaer A, Petersen CM | display-authors = 6 | title = SorLA controls neurotrophic activity by sorting of GDNF and its receptors GFRα1 and RET | journal = Cell Reports | volume = 3 | issue = 1 | pages = 186–99 | date = January 2013 | pmid = 23333276 | doi = 10.1016/j.celrep.2012.12.011 | doi-access = free }}</ref> The mature form of the protein is a ligand for the product of the [[RET proto-oncogene|RET]] (rearranged during transfection) protooncogene. In addition to the transcript encoding GDNF, two additional alternative transcripts encoding distinct proteins, referred to as astrocyte-derived trophic factors, have also been described. Mutations in this gene may be associated with [[Hirschprung's disease|Hirschsprung's disease]].<ref name="entrez"/>


GDNF has the ability to activate the ERK-1 and ERK-2 isoforms of MAP kinase in sympathetic neurons as well as P13K/AKT pathways via activation of its [[receptor tyrosine kinases]].<ref>{{cite journal | pmid=8945474 | title=Neurturin, a relative of glial-cell-line-derived neurotrophic factor}}</ref><ref>{{cite journal | pmid=26829643 | title=Biology of GDNF and its receptors - Relevance for disorders of the central nervous system}}</ref> It can also activate Src-family kinases through its GFRα1 receptor.<ref>{{cite journal | pmid=11988777 | title=The GDNF family: signalling, biological functions and therapeutic value}}</ref>
GDNF has the ability to activate the ERK-1 and ERK-2 isoforms of MAP kinase in sympathetic neurons as well as P13K/AKT pathways via activation of its [[receptor tyrosine kinases]].<ref name="Neurturin, a relative of glial-cell">{{cite journal | vauthors = Kotzbauer PT, Lampe PA, Heuckeroth RO, Golden JP, Creedon DJ, Johnson EM, Milbrandt J | title = Neurturin, a relative of glial-cell-line-derived neurotrophic factor | journal = Nature | volume = 384 | issue = 6608 | pages = 467–70 | date = December 1996 | pmid = 8945474 | doi = 10.1038/384467a0 | bibcode = 1996Natur.384..467K | s2cid = 4238843 }}</ref><ref name="Biology of GDNF and its receptors">{{cite journal | vauthors = Ibáñez CF, Andressoo JO | title = Biology of GDNF and its receptors - Relevance for disorders of the central nervous system | journal = Neurobiology of Disease | volume = 97 | issue = Pt B | pages = 80–89 | date = January 2017 | pmid = 26829643 | doi = 10.1016/j.nbd.2016.01.021 | s2cid = 17588722 }}</ref> It can also activate Src-family kinases through its GFRα1 receptor.<ref>{{cite journal | vauthors = Airaksinen MS, Saarma M | title = The GDNF family: signalling, biological functions and therapeutic value | journal = Nature Reviews. Neuroscience | volume = 3 | issue = 5 | pages = 383–94 | date = May 2002 | pmid = 11988777 | doi = 10.1038/nrn812 | s2cid = 2480120 }}</ref>


The most prominent feature of GDNF is its ability to support the survival of [[dopaminergic]]<ref name="pmid = 12832538">{{cite journal | vauthors = Oo TF, Kholodilov N, Burke RE | title = Regulation of natural cell death in dopaminergic neurons of the substantia nigra by striatal glial cell line-derived neurotrophic factor in vivo. | journal = Journal of Neuroscience | volume = 23 | issue = 12 | pages = 5141–8 | date = Jun 2003 | pmid = 12832538 | doi = 10.1523/JNEUROSCI.23-12-05141.2003 | pmc = 6741204 | doi-access = free }}</ref> and [[motorneuron]]s.{{cn|date=February 2019}} It prevents apoptosis in motor neurons during development, decreases the overall loss of neurons during development, rescues cells from axotomy-induced death, and prevents chronic degeneration.<ref>{{cite journal | pmid=32897420 | title=GDNF synthesis, signaling, and retrograde transport in motor neurons}}</ref>
The most prominent feature of GDNF is its ability to support the survival of dopaminergic<ref name="pmid = 12832538">{{cite journal | vauthors = Oo TF, Kholodilov N, Burke RE | title = Regulation of natural cell death in dopaminergic neurons of the substantia nigra by striatal glial cell line-derived neurotrophic factor in vivo | journal = The Journal of Neuroscience | volume = 23 | issue = 12 | pages = 5141–8 | date = June 2003 | pmid = 12832538 | pmc = 6741204 | doi = 10.1523/JNEUROSCI.23-12-05141.2003 | doi-access = free }}</ref> and [[motorneuron|motor neuron]]s.{{citation needed|date=February 2019}} It prevents apoptosis in motor neurons during development, decreases the overall loss of neurons during development, rescues cells from axotomy-induced death, and prevents chronic degeneration.<ref name="paper1"/>


These neuronal populations die in the course of [[Parkinson's disease]] and [[amyotrophic lateral sclerosis]] (ALS). GDNF also regulates [[kidney]] development and [[Sertoli cell|spermatogenesis]], and has a powerful and rapid negative (ameliorating) effect on [[alcohol consumption]].<ref name="pmid18541917">{{cite journal | vauthors = Carnicella S, Kharazia V, Jeanblanc J, Janak PH, Ron D | title = GDNF is a fast-acting potent inhibitor of alcohol consumption and relapse | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 23 | pages = 8114–9 | date = Jun 2008 | pmid = 18541917 | pmc = 2423415 | doi = 10.1073/pnas.0711755105 | bibcode = 2008PNAS..105.8114C }}</ref> GDNF also promotes [[hair follicle]] formation and cutaneous [[wound healing]] by targeting resident hair follicle stem cells (BSCs) in the bulge compartment.
These neuronal populations die in the course of [[Parkinson's disease]] and [[amyotrophic lateral sclerosis]] (ALS). GDNF also regulates [[kidney]] development and [[Sertoli cell|spermatogenesis]], and has a powerful and rapid negative (ameliorating) effect on [[alcohol consumption]].<ref name="pmid18541917">{{cite journal | vauthors = Carnicella S, Kharazia V, Jeanblanc J, Janak PH, Ron D | title = GDNF is a fast-acting potent inhibitor of alcohol consumption and relapse | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 23 | pages = 8114–9 | date = June 2008 | pmid = 18541917 | pmc = 2423415 | doi = 10.1073/pnas.0711755105 | bibcode = 2008PNAS..105.8114C | doi-access = free }}</ref> GDNF also promotes [[hair follicle]] formation and cutaneous [[wound healing]] by targeting resident hair follicle stem cells (BSCs) in the bulge compartment.<ref name="pmid32566252">{{cite journal | vauthors = Lisse TS, Sharma M, Vishlaghi N, Pullagura SR, Braun RE | title = GDNF promotes hair formation and cutaneous wound healing by targeting bulge stem cells | journal = npj Regenerative Medicine | volume = 5 | issue = 13 | pages = 13 | date = Jun 2020 | pmid = 32566252 | pmc = 7293257 | doi = 10.1038/s41536-020-0098-z }}</ref>
<ref name="pmid32566252">{{cite journal | vauthors = Lisse TS, Sharma M, Vishlaghi N, Pullagura SR, Braun RE | title = GDNF Promotes Hair Formation and Cutaneous Wound Healing by Targeting Bulge Stem Cells | journal = NPJ Regenerative Medicine | volume = 5 | issue = 13 | date = Jun 2020 | page = 13 | pmid = 32566252 | pmc = 7293257 | doi = 10.1038/s41536-020-0098-z }}</ref>


== Structure ==
== Structure ==
GDNF has a structure that is similar to [[TGF beta 2]].<ref>{{cite journal | pmid=8945474 | title=Neurturin, a relative of glial-cell-line-derived neurotrophic factor}}</ref> GDNF has two finger-like structures that interact with the [[GFRα1]] receptor. [[N-linked glycosylation]], which occurs during the secretion of pro-GDNF, takes place at the tip of one of the finger-like structures. The C-terminal of mature GDNF plays an important role in binding with both [[Ret]] and the [[GFRα1]] receptor. The C-terminus forms a loop out of the interactions between [[cysteine]]s Cys131, Cy133, Cys68, and Cys 72.<ref name="paper1"></ref>
GDNF has a structure that is similar to [[TGF beta 2]].<ref name="Neurturin, a relative of glial-cell"/> GDNF has two finger-like structures that interact with the [[GFRα1]] receptor. [[N-linked glycosylation]], which occurs during the secretion of pro-GDNF, takes place at the tip of one of the finger-like structures. The C-terminal of mature GDNF plays an important role in binding with both [[RET proto-oncogene|Ret]] and the [[GFRα1]] receptor. The C-terminus forms a loop out of the interactions between [[cysteine]]s Cys131, Cy133, Cys68, and Cys 72.<ref name="paper1" />


== Interactions ==
== Interactions ==
⚫
Glial cell line-derived neurotrophic factor has been shown to [[Protein-protein interaction|interact]] with [[GFRA1 (gene)|GFRA1]]<ref name="paper1" /><ref name=pmid10829012>{{cite journal | vauthors = Cik M, Masure S, Lesage AS, Van Der Linden I, Van Gompel P, Pangalos MN, Gordon RD, Leysen JE | display-authors = 6 | title = Binding of GDNF and neurturin to human GDNF family receptor alpha 1 and 2. Influence of cRET and cooperative interactions | journal = The Journal of Biological Chemistry | volume = 275 | issue = 36 | pages = 27505–12 | date = September 2000 | pmid = 10829012 | doi = 10.1074/jbc.M000306200 | doi-access = free }}</ref> and [[GDNF family receptor alpha 1]]. The activity of GDNF, as well as other GFLs, is mediated by RET receptor tyrosine kinase. In order for the receptor to modulate GDNF activity, GDNF must also be bound to GFRα1.<ref name="Neurturin, a relative of glial-cell"/> The intensity and duration of RET signaling can likewise be monitored by the GPI-anchor of GFRα1 by interacting with compartments of the cell membrane, such as lipid rafts or cleavage by [[phospholipase]]s.<ref name="Biology of GDNF and its receptors"/> In cells that lack RET, some [[GDNF family ligand]] members also have the ability to be activated through the [[neural cell adhesion molecule]] (NCAM). GDNF can associate with NCAM through its GFRα1 GPI-anchor. The association between GDNF and NCAM results in the activation of cytoplasmic protein tyrosine kinases Fyn and FAK.<ref>{{cite journal | vauthors = Paratcha G, Ledda F, Ibáñez CF | title = The neural cell adhesion molecule NCAM is an alternative signaling receptor for GDNF family ligands | journal = Cell | volume = 113 | issue = 7 | pages = 867–79 | date = June 2003 | pmid = 12837245 | doi = 10.1016/s0092-8674(03)00435-5 | doi-access = free }}</ref>

⚫
Glial cell line-derived neurotrophic factor has been shown to [[Protein-protein interaction|interact]] with [[GFRA1 (gene)|GFRA1]]<ref name="paper1"></ref><ref name=pmid10829012>{{cite journal | vauthors = Cik M, Masure S, Lesage AS, Van Der Linden I, Van Gompel P, Pangalos MN, Gordon RD, Leysen JE | title = Binding of GDNF and neurturin to human GDNF family receptor alpha 1 and 2. Influence of cRET and cooperative interactions | journal = The Journal of Biological Chemistry | volume = 275 | issue = 36 | pages = 27505–12 | date = Sep 2000 | pmid = 10829012 | doi = 10.1074/jbc.M000306200 | doi-access = free }}</ref> and [[GDNF family receptor alpha 1]]. The activity of GDNF, as well as other GFLs, is mediated by RET receptor tyrosine kinase. In order for the receptor to modulate GDNF activity, GDNF must also be bound to GFRα1.<ref>{{cite journal | pmid=8945474 | title=Neurturin, a relative of glial-cell-line-derived neurotrophic factor}}</ref> The intensity and duration of RET signaling can likewise be monitored by the GPI-anchor of GFRα1 by interacting with compartments of the cell membrane, such as lipid rafts or cleavage by [[phospholipase]]s.<ref>{{cite journal | pmid=26829643 | title=Biology of GDNF and its receptors - Relevance for disorders of the central nervous system}}</ref> In cells that lack RET, some [[GDNF family ligand]] members also have the ability to be activated through the [[neural cell adhesion molecule]] (NCAM). GDNF can associate with NCAM through its GFRα1 GPI-anchor. The association between GDNF and NCAM results in the activation of cytoplasmic protein tyrosine kinases Fyn and FAK.<ref>{{cite journal | pmid=12837245 | title=The neural cell adhesion molecule NCAM is an alternative signaling receptor for GDNF family ligands}}</ref>


== Potential as therapeutics ==
== Potential as therapeutics ==
GDNF has been investigated as a treatment for [[Parkinson's disease]], though early research has not shown a significant effect.<ref name="vastag"/><ref>{{cite web |title=Intermittent Bilateral Intraputamenal Treatment with GDNF |url=https://www.michaeljfox.org/foundation/grant-detail.php?grant_id=664 |website=The Michael J. Fox Foundation for Parkinson's Research {{!}} Parkinson's Disease}}</ref><ref>{{Cite web |url=https://www.nature.com/news/2010/100818/full/466916a.html |title=Biotechnology: Crossing the barrier |last=Brian Vastag |website=Nature |publisher=Springer Nature |access-date=2019-03-27}}</ref> [[Vitamin D]] potently induces GDNF expression.<ref name="Vit D GDNF">{{cite journal|author1=Eserian JK|title=Vitamin D as an effective treatment approach for drug abuse and addiction|journal=Journal of Medical Hypotheses and Ideas|date=July 2013|volume=7|issue=2|pages=35–39|doi=10.1016/j.jmhi.2013.02.001|quote=Vitamin D is a potent inducer of endogenous GDNF. The most prominent feature of GDNF is its ability to support the survival of dopaminergic neurons.|doi-access=free}}</ref>
GDNF has been investigated as a treatment for Parkinson's disease, though early research has not shown a significant effect.<ref name="vastag"/><ref>{{cite web |title=Intermittent Bilateral Intraputamenal Treatment with GDNF |url=https://www.michaeljfox.org/foundation/grant-detail.php?grant_id=664 |website=The Michael J. Fox Foundation for Parkinson's Research {{!}} Parkinson's Disease}}</ref> [[Vitamin D]] potently induces GDNF expression.<ref name="Vit D GDNF">{{cite journal|author1=Eserian JK|title=Vitamin D as an effective treatment approach for drug abuse and addiction|journal=Journal of Medical Hypotheses and Ideas|date=July 2013|volume=7|issue=2|pages=35–39|doi=10.1016/j.jmhi.2013.02.001|quote=Vitamin D is a potent inducer of endogenous GDNF. The most prominent feature of GDNF is its ability to support the survival of dopaminergic neurons.|doi-access=free}}</ref>


In 2012, the [[University of Bristol]] began a five-year clinical trial on Parkinson's sufferers, in which surgeons introduced a port into the skull of each of the 41 participants through which the drug could be delivered, in order to enable it to reach the damaged cells directly.<ref>{{cite web|url=https://www.bbc.co.uk/news/av/stories-47483307/the-radical-drug-trial-hoping-for-a-miracle-parkinson-s-cure|title=The radical drug trial hoping for a miracle Parkinson's cure|website=BBC News|access-date=10 March 2019}}</ref> The results of the double-blind trial, where half the participants were randomly assigned to receive regular infusions of GDNF and the other half placebo infusions, did not show a statistically significant difference between the active treatment group and those who received placebo, but did confirm the effects on damaged brain cells.<ref>{{cite web|url=https://www.parkinsons.org.uk/news/gdnf-clinical-trial-offers-hope-restoring-brain-cells-damaged-parkinsons|title=GDNF clinical trial offers hope of restoring brain cells damaged in Parkinson's|date=27 February 2019|website=Parkinsons UK|access-date=10 March 2019}}</ref> The trial was funded by Parkinson's UK with support from The Cure Parkinson's Trust, whose founder, [[Tom Isaacs (fundraiser)|Tom Isaacs]], was one of the participants.<ref>{{Cite web |url=https://www.bristol.ac.uk/news/2019/february/gdnf-trial.html |title=Pioneering trial offers hope for restoring brain cells damaged in Parkinson's |date=2019-02-19 |website=University of Bristol}}</ref>
In 2012, the [[University of Bristol]] began a five-year clinical trial on Parkinson's sufferers, in which surgeons introduced a port into the skull of each of the 41 participants through which the drug could be delivered, in order to enable it to reach the damaged cells directly.<ref>{{cite news|url=https://www.bbc.co.uk/news/av/stories-47483307/the-radical-drug-trial-hoping-for-a-miracle-parkinson-s-cure|title=The radical drug trial hoping for a miracle Parkinson's cure|work=BBC News|access-date=10 March 2019|archive-date=10 March 2019|archive-url=https://web.archive.org/web/20190310124514/https://www.bbc.co.uk/news/av/stories-47483307/the-radical-drug-trial-hoping-for-a-miracle-parkinson-s-cure|url-status=live}}</ref> The results of the double-blind trial, where half the participants were randomly assigned to receive regular infusions of GDNF and the other half placebo infusions, did not show a statistically significant difference between the active treatment group and those who received placebo, but did confirm the effects on damaged brain cells.<ref>{{cite web|url=https://www.parkinsons.org.uk/news/gdnf-clinical-trial-offers-hope-restoring-brain-cells-damaged-parkinsons|title=GDNF clinical trial offers hope of restoring brain cells damaged in Parkinson's|date=27 February 2019|website=Parkinsons UK|access-date=10 March 2019|archive-date=27 March 2019|archive-url=https://web.archive.org/web/20190327134330/https://www.parkinsons.org.uk/news/gdnf-clinical-trial-offers-hope-restoring-brain-cells-damaged-parkinsons|url-status=live}}</ref> The trial was funded by Parkinson's UK with support from The Cure Parkinson's Trust, whose founder, [[Tom Isaacs (fundraiser)|Tom Isaacs]], was one of the participants.<ref>{{Cite web |url=https://www.bristol.ac.uk/news/2019/february/gdnf-trial.html |title=Pioneering trial offers hope for restoring brain cells damaged in Parkinson's |date=2019-02-19 |website=University of Bristol |access-date=2019-03-27 |archive-date=2019-03-27 |archive-url=https://web.archive.org/web/20190327162522/https://www.bristol.ac.uk/news/2019/february/gdnf-trial.html |url-status=live }}</ref>

==Neuropsychopharmacology==
Administration of the African hallucinogen [[ibogaine]] potently increases GDNF expression in the [[ventral tegmental area]], which is the mechanism behind the alkaloid's anti-addictive effect.<ref name="pmid15659598">{{cite journal | vauthors = He DY, McGough NN, Ravindranathan A, Jeanblanc J, Logrip ML, Phamluong K, Janak PH, Ron D | display-authors = 6 | title = Glial cell line-derived neurotrophic factor mediates the desirable actions of the anti-addiction drug ibogaine against alcohol consumption | journal = The Journal of Neuroscience | volume = 25 | issue = 3 | pages = 619–28 | date = January 2005 | pmid = 15659598 | pmc = 1193648 | doi = 10.1523/JNEUROSCI.3959-04.2005 }}</ref> Rodent models for a non-psychedelic analogue of this compound show promise in promoting GDNF expression without the hallucinogenic or cardiotoxic effects well documented for ibogaine.<ref name="pmid33299186">{{cite journal | vauthors = Cameron LP, Tombari RJ, Lu J, Pell AJ, Hurley ZQ, Ehinger Y, Vargas MV, McCarroll MN, Taylor JC, Myers-Turnbull D, Liu T, Yaghoobi B, Laskowski LJ, Anderson EI, Zhang G, Viswanathan J, Brown BM, Tjia M, Dunlap LE, Rabow ZT, Fiehn O, Wulff H, McCorvy JD, Lein PJ, Kokel D, Ron D, Peters J, Zuo Y, Olson DE | display-authors = 6 | title = A non-hallucinogenic psychedelic analogue with therapeutic potential | journal = Nature | volume = 589 | issue = 7842 | pages = 474–479 | date = January 2021 | pmid = 33299186 | doi = 10.1038/s41586-020-3008-z | pmc = 7874389 | bibcode = 2021Natur.589..474C }}</ref>

There is evidence, that Gdnf is an alcohol-responsive [[gene]] upregulated during short-term [[Alcohol (drug)|alcohol]] intake but downregulated during withdrawal from excessive alcohol intake.<ref>{{cite journal | vauthors = Barak S, Ahmadiantehrani S, Logrip ML, Ron D | title = GDNF and alcohol use disorder | journal = Addiction Biology | volume = 24 | issue = 3 | pages = 335–343 | date = May 2019 | pmid = 29726054 | doi = 10.1111/adb.12628 | pmc = 6215739 }}</ref> Specifically, one study showed that alcohol withdrawal alters the expression of Gdnf in [[addiction]] related brain areas like the [[ventral tegmental area]] (VTA) and the [[Nucleus Accumbens]] as well as [[DNA methylation]] of the Gdnf gene in rats.<ref>{{cite journal | vauthors = Maier HB, Neyazi M, Neyazi A, Hillemacher T, Pathak H, Rhein M, Bleich S, Goltseker K, Sadot-Sogrin Y, Even-Chen O, Frieling H, Barak S | display-authors = 6 | title = Alcohol consumption alters Gdnf promoter methylation and expression in rats | journal = Journal of Psychiatric Research | volume = 121 | pages = 1–9 | date = February 2020 | pmid = 31710958 | doi = 10.1016/j.jpsychires.2019.10.020 | s2cid = 207964134 }}</ref>


== References ==
== References ==
{{reflist|33em}}{{clear}}
{{reflist|33em}}


== Further reading ==
== Further reading ==
{{refbegin|33em}}
{{refbegin|33em}}
* {{cite journal | vauthors = Hofstra RM, Osinga J, Buys CH | title = Mutations in Hirschsprung disease: when does a mutation contribute to the phenotype | journal = European Journal of Human Genetics | volume = 5 | issue = 4 | pages = 180–5 | year = 1998 | pmid = 9359036 | doi = 10.1159/000484760}}
* {{cite journal | vauthors = Hofstra RM, Osinga J, Buys CH | title = Mutations in Hirschsprung disease: when does a mutation contribute to the phenotype | journal = European Journal of Human Genetics | volume = 5 | issue = 4 | pages = 180–5 | year = 1998 | pmid = 9359036 | doi = 10.1159/000484760 }}
* {{cite journal | vauthors = Martucciello G, Ceccherini I, Lerone M, Jasonni V | title = Pathogenesis of Hirschsprung's disease | journal = Journal of Pediatric Surgery | volume = 35 | issue = 7 | pages = 1017–25 | date = Jul 2000 | pmid = 10917288 | doi = 10.1053/jpsu.2000.7763 }}
* {{cite journal | vauthors = Martucciello G, Ceccherini I, Lerone M, Jasonni V | title = Pathogenesis of Hirschsprung's disease | journal = Journal of Pediatric Surgery | volume = 35 | issue = 7 | pages = 1017–25 | date = July 2000 | pmid = 10917288 | doi = 10.1053/jpsu.2000.7763 }}
* {{cite journal | vauthors = Schindelhauer D, Schuffenhauer S, Gasser T, Steinkasserer A, Meitinger T | title = The gene coding for glial cell line derived neurotrophic factor (GDNF) maps to chromosome 5p12-p13.1 | journal = Genomics | volume = 28 | issue = 3 | pages = 605–7 | date = Aug 1995 | pmid = 7490108 | doi = 10.1006/geno.1995.1202 }}
* {{cite journal | vauthors = Schindelhauer D, Schuffenhauer S, Gasser T, Steinkasserer A, Meitinger T | title = The gene coding for glial cell line derived neurotrophic factor (GDNF) maps to chromosome 5p12-p13.1 | journal = Genomics | volume = 28 | issue = 3 | pages = 605–7 | date = August 1995 | pmid = 7490108 | doi = 10.1006/geno.1995.1202 }}
* {{cite journal | vauthors = Tomac A, Lindqvist E, Lin LF, Ogren SO, Young D, Hoffer BJ, Olson L | title = Protection and repair of the nigrostriatal dopaminergic system by GDNF in vivo | journal = Nature | volume = 373 | issue = 6512 | pages = 335–9 | date = Jan 1995 | pmid = 7830766 | doi = 10.1038/373335a0 | bibcode = 1995Natur.373..335T | s2cid = 4340992 }}
* {{cite journal | vauthors = Tomac A, Lindqvist E, Lin LF, Ogren SO, Young D, Hoffer BJ, Olson L | title = Protection and repair of the nigrostriatal dopaminergic system by GDNF in vivo | journal = Nature | volume = 373 | issue = 6512 | pages = 335–9 | date = January 1995 | pmid = 7830766 | doi = 10.1038/373335a0 | s2cid = 4340992 | bibcode = 1995Natur.373..335T | doi-access = free }}
* {{cite journal | vauthors = Oppenheim RW, Houenou LJ, Johnson JE, Lin LF, Li L, Lo AC, Newsome AL, Prevette DM, Wang S | title = Developing motor neurons rescued from programmed and axotomy-induced cell death by GDNF | journal = Nature | volume = 373 | issue = 6512 | pages = 344–6 | date = Jan 1995 | pmid = 7830769 | doi = 10.1038/373344a0 | bibcode = 1995Natur.373..344O | s2cid = 2863274 }}
* {{cite journal | vauthors = Oppenheim RW, Houenou LJ, Johnson JE, Lin LF, Li L, Lo AC, Newsome AL, Prevette DM, Wang S | display-authors = 6 | title = Developing motor neurons rescued from programmed and axotomy-induced cell death by GDNF | journal = Nature | volume = 373 | issue = 6512 | pages = 344–6 | date = January 1995 | pmid = 7830769 | doi = 10.1038/373344a0 | s2cid = 2863274 | bibcode = 1995Natur.373..344O }}
* {{cite journal | vauthors = Schaar DG, Sieber BA, Sherwood AC, Dean D, Mendoza G, Ramakrishnan L, Dreyfus CF, Black IB | title = Multiple astrocyte transcripts encode nigral trophic factors in rat and human | journal = Experimental Neurology | volume = 130 | issue = 2 | pages = 387–93 | date = Dec 1994 | pmid = 7867768 | doi = 10.1006/exnr.1994.1218 | s2cid = 37574956 }}
* {{cite journal | vauthors = Schaar DG, Sieber BA, Sherwood AC, Dean D, Mendoza G, Ramakrishnan L, Dreyfus CF, Black IB | display-authors = 6 | title = Multiple astrocyte transcripts encode nigral trophic factors in rat and human | journal = Experimental Neurology | volume = 130 | issue = 2 | pages = 387–93 | date = December 1994 | pmid = 7867768 | doi = 10.1006/exnr.1994.1218 | s2cid = 37574956 }}
* {{cite journal | vauthors = Lin LF, Doherty DH, Lile JD, Bektesh S, Collins F | title = GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons | journal = Science | volume = 260 | issue = 5111 | pages = 1130–2 | date = May 1993 | pmid = 8493557 | doi = 10.1126/science.8493557 | bibcode = 1993Sci...260.1130L }}
* {{cite journal | vauthors = Lin LF, Doherty DH, Lile JD, Bektesh S, Collins F | title = GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons | journal = Science | volume = 260 | issue = 5111 | pages = 1130–2 | date = May 1993 | pmid = 8493557 | doi = 10.1126/science.8493557 | bibcode = 1993Sci...260.1130L }}
* {{cite journal | vauthors = Bermingham N, Hillermann R, Gilmour F, Martin JE, Fisher EM | title = Human glial cell line-derived neurotrophic factor (GDNF) maps to chromosome 5 | journal = Human Genetics | volume = 96 | issue = 6 | pages = 671–3 | date = Dec 1995 | pmid = 8522325 | doi = 10.1007/BF00210297 | s2cid = 30960307 }}
* {{cite journal | vauthors = Bermingham N, Hillermann R, Gilmour F, Martin JE, Fisher EM | title = Human glial cell line-derived neurotrophic factor (GDNF) maps to chromosome 5 | journal = Human Genetics | volume = 96 | issue = 6 | pages = 671–3 | date = December 1995 | pmid = 8522325 | doi = 10.1007/BF00210297 | s2cid = 30960307 }}
* {{cite journal | vauthors = Gash DM, Zhang Z, Ovadia A, Cass WA, Yi A, Simmerman L, Russell D, Martin D, Lapchak PA, Collins F, Hoffer BJ, Gerhardt GA | title = Functional recovery in parkinsonian monkeys treated with GDNF | journal = Nature | volume = 380 | issue = 6571 | pages = 252–5 | date = Mar 1996 | pmid = 8637574 | doi = 10.1038/380252a0 | bibcode = 1996Natur.380..252G | s2cid = 4313985 }}
* {{cite journal | vauthors = Gash DM, Zhang Z, Ovadia A, Cass WA, Yi A, Simmerman L, Russell D, Martin D, Lapchak PA, Collins F, Hoffer BJ, Gerhardt GA | display-authors = 6 | title = Functional recovery in parkinsonian monkeys treated with GDNF | journal = Nature | volume = 380 | issue = 6571 | pages = 252–5 | date = March 1996 | pmid = 8637574 | doi = 10.1038/380252a0 | s2cid = 4313985 | bibcode = 1996Natur.380..252G }}
* {{cite journal | vauthors = Jing S, Wen D, Yu Y, Holst PL, Luo Y, Fang M, Tamir R, Antonio L, Hu Z, Cupples R, Louis JC, Hu S, Altrock BW, Fox GM | title = GDNF-induced activation of the ret protein tyrosine kinase is mediated by GDNFR-alpha, a novel receptor for GDNF | journal = Cell | volume = 85 | issue = 7 | pages = 1113–24 | date = Jun 1996 | pmid = 8674117 | doi = 10.1016/S0092-8674(00)81311-2 | s2cid = 1724567 }}
* {{cite journal | vauthors = Jing S, Wen D, Yu Y, Holst PL, Luo Y, Fang M, Tamir R, Antonio L, Hu Z, Cupples R, Louis JC, Hu S, Altrock BW, Fox GM | display-authors = 6 | title = GDNF-induced activation of the ret protein tyrosine kinase is mediated by GDNFR-alpha, a novel receptor for GDNF | journal = Cell | volume = 85 | issue = 7 | pages = 1113–24 | date = June 1996 | pmid = 8674117 | doi = 10.1016/S0092-8674(00)81311-2 | s2cid = 1724567 | doi-access = free }}
* {{cite journal | vauthors = Angrist M, Bolk S, Halushka M, Lapchak PA, Chakravarti A | title = Germline mutations in glial cell line-derived neurotrophic factor (GDNF) and RET in a Hirschsprung disease patient | journal = Nature Genetics | volume = 14 | issue = 3 | pages = 341–4 | date = Nov 1996 | pmid = 8896568 | doi = 10.1038/ng1196-341 | s2cid = 24350470 }}
* {{cite journal | vauthors = Angrist M, Bolk S, Halushka M, Lapchak PA, Chakravarti A | title = Germline mutations in glial cell line-derived neurotrophic factor (GDNF) and RET in a Hirschsprung disease patient | journal = Nature Genetics | volume = 14 | issue = 3 | pages = 341–4 | date = November 1996 | pmid = 8896568 | doi = 10.1038/ng1196-341 | s2cid = 24350470 }}
* {{cite journal | vauthors = Salomon R, Attié T, Pelet A, Bidaud C, Eng C, Amiel J, Sarnacki S, Goulet O, Ricour C, Nihoul-Fékété C, Munnich A, Lyonnet S | title = Germline mutations of the RET ligand GDNF are not sufficient to cause Hirschsprung disease | journal = Nature Genetics | volume = 14 | issue = 3 | pages = 345–7 | date = Nov 1996 | pmid = 8896569 | doi = 10.1038/ng1196-345 | s2cid = 22375940 }}
* {{cite journal | vauthors = Salomon R, Attié T, Pelet A, Bidaud C, Eng C, Amiel J, Sarnacki S, Goulet O, Ricour C, Nihoul-Fékété C, Munnich A, Lyonnet S | display-authors = 6 | title = Germline mutations of the RET ligand GDNF are not sufficient to cause Hirschsprung disease | journal = Nature Genetics | volume = 14 | issue = 3 | pages = 345–7 | date = November 1996 | pmid = 8896569 | doi = 10.1038/ng1196-345 | s2cid = 22375940 }}
* {{cite journal | vauthors = Ivanchuk SM, Myers SM, Eng C, Mulligan LM | title = De novo mutation of GDNF, ligand for the RET/GDNFR-alpha receptor complex, in Hirschsprung disease | journal = Human Molecular Genetics | volume = 5 | issue = 12 | pages = 2023–6 | date = Dec 1996 | pmid = 8968758 | doi = 10.1093/hmg/5.12.2023 | doi-access = free }}
* {{cite journal | vauthors = Ivanchuk SM, Myers SM, Eng C, Mulligan LM | title = De novo mutation of GDNF, ligand for the RET/GDNFR-alpha receptor complex, in Hirschsprung disease | journal = Human Molecular Genetics | volume = 5 | issue = 12 | pages = 2023–6 | date = December 1996 | pmid = 8968758 | doi = 10.1093/hmg/5.12.2023 | doi-access = free }}
* {{cite journal | vauthors = Haniu M, Hui J, Young Y, Le J, Katta V, Lee R, Shimamoto G, Rohde MF | title = Glial cell line-derived neurotrophic factor: selective reduction of the intermolecular disulfide linkage and characterization of its disulfide structure | journal = Biochemistry | volume = 35 | issue = 51 | pages = 16799–805 | date = Dec 1996 | pmid = 8988018 | doi = 10.1021/bi9605550 }}
* {{cite journal | vauthors = Haniu M, Hui J, Young Y, Le J, Katta V, Lee R, Shimamoto G, Rohde MF | display-authors = 6 | title = Glial cell line-derived neurotrophic factor: selective reduction of the intermolecular disulfide linkage and characterization of its disulfide structure | journal = Biochemistry | volume = 35 | issue = 51 | pages = 16799–805 | date = December 1996 | pmid = 8988018 | doi = 10.1021/bi9605550 }}
* {{cite journal | vauthors = Bär KJ, Facer P, Williams NS, Tam PK, Anand P | title = Glial-derived neurotrophic factor in human adult and fetal intestine and in Hirschsprung's disease | journal = Gastroenterology | volume = 112 | issue = 4 | pages = 1381–5 | date = Apr 1997 | pmid = 9098026 | doi = 10.1016/S0016-5085(97)70154-9 }}
* {{cite journal | vauthors = Bär KJ, Facer P, Williams NS, Tam PK, Anand P | title = Glial-derived neurotrophic factor in human adult and fetal intestine and in Hirschsprung's disease | journal = Gastroenterology | volume = 112 | issue = 4 | pages = 1381–5 | date = April 1997 | pmid = 9098026 | doi = 10.1016/S0016-5085(97)70154-9 | doi-access = free }}
* {{cite journal | vauthors = Jing S, Yu Y, Fang M, Hu Z, Holst PL, Boone T, Delaney J, Schultz H, Zhou R, Fox GM | title = GFRalpha-2 and GFRalpha-3 are two new receptors for ligands of the GDNF family | journal = The Journal of Biological Chemistry | volume = 272 | issue = 52 | pages = 33111–7 | date = Dec 1997 | pmid = 9407096 | doi = 10.1074/jbc.272.52.33111 | doi-access = free }}
* {{cite journal | vauthors = Jing S, Yu Y, Fang M, Hu Z, Holst PL, Boone T, Delaney J, Schultz H, Zhou R, Fox GM | display-authors = 6 | title = GFRalpha-2 and GFRalpha-3 are two new receptors for ligands of the GDNF family | journal = The Journal of Biological Chemistry | volume = 272 | issue = 52 | pages = 33111–7 | date = December 1997 | pmid = 9407096 | doi = 10.1074/jbc.272.52.33111 | doi-access = free }}
* {{cite journal | vauthors = Eng C, Myers SM, Kogon MD, Sanicola M, Hession C, Cate RL, Mulligan LM | title = Genomic structure and chromosomal localization of the human GDNFR-alpha gene | journal = Oncogene | volume = 16 | issue = 5 | pages = 597–601 | date = Feb 1998 | pmid = 9482105 | doi = 10.1038/sj.onc.1201573 | doi-access = free }}
* {{cite journal | vauthors = Eng C, Myers SM, Kogon MD, Sanicola M, Hession C, Cate RL, Mulligan LM | title = Genomic structure and chromosomal localization of the human GDNFR-alpha gene | journal = Oncogene | volume = 16 | issue = 5 | pages = 597–601 | date = February 1998 | pmid = 9482105 | doi = 10.1038/sj.onc.1201573 | doi-access = free }}
* {{cite journal | vauthors = Amiel J, Salomon R, Attié T, Pelet A, Trang H, Mokhtari M, Gaultier C, Munnich A, Lyonnet S | title = Mutations of the RET-GDNF signaling pathway in Ondine's curse | journal = American Journal of Human Genetics | volume = 62 | issue = 3 | pages = 715–7 | date = Mar 1998 | pmid = 9497256 | pmc = 1376953 | doi = 10.1086/301759 }}
* {{cite journal | vauthors = Amiel J, Salomon R, Attié T, Pelet A, Trang H, Mokhtari M, Gaultier C, Munnich A, Lyonnet S | display-authors = 6 | title = Mutations of the RET-GDNF signaling pathway in Ondine's curse | journal = American Journal of Human Genetics | volume = 62 | issue = 3 | pages = 715–7 | date = March 1998 | pmid = 9497256 | pmc = 1376953 | doi = 10.1086/301759 }}
* {{cite journal | vauthors = Yamaguchi Y, Wada T, Suzuki F, Takagi T, Hasegawa J, Handa H | title = Casein kinase II interacts with the bZIP domains of several transcription factors | journal = Nucleic Acids Research | volume = 26 | issue = 16 | pages = 3854–61 | date = Aug 1998 | pmid = 9685505 | pmc = 147779 | doi = 10.1093/nar/26.16.3854 }}
* {{cite journal | vauthors = Yamaguchi Y, Wada T, Suzuki F, Takagi T, Hasegawa J, Handa H | title = Casein kinase II interacts with the bZIP domains of several transcription factors | journal = Nucleic Acids Research | volume = 26 | issue = 16 | pages = 3854–61 | date = August 1998 | pmid = 9685505 | pmc = 147779 | doi = 10.1093/nar/26.16.3854 }}
* {{cite journal | vauthors = Oo TF, Kholodilov N, Burke RE | title = Regulation of natural cell death in dopaminergic neurons of the substantia nigra by striatal glial cell line-derived neurotrophic factor in vivo. | journal = Journal of Neuroscience | volume = 23 | issue = 12 | pages = 5141–8 | date = Jun 2003 | pmid = 12832538 | doi = 10.1523/JNEUROSCI.23-12-05141.2003 | pmc = 6741204 | doi-access = free }}
* {{cite journal | vauthors = Oo TF, Kholodilov N, Burke RE | title = Regulation of natural cell death in dopaminergic neurons of the substantia nigra by striatal glial cell line-derived neurotrophic factor in vivo | journal = The Journal of Neuroscience | volume = 23 | issue = 12 | pages = 5141–8 | date = June 2003 | pmid = 12832538 | pmc = 6741204 | doi = 10.1523/JNEUROSCI.23-12-05141.2003 | doi-access = free }}
{{refend}}
{{refend}}


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[[Category:TGFβ domain]]
[[Category:Proteins]]
[[Category:Proteins]]
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[[Category:TGFβ domain]]

Latest revision as of 15:39, 7 June 2024

GDNF
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesGDNF, ATF1, ATF2, HFB1-HSCR3, glial cell derived neurotrophic factor, ATF
External IDsOMIM: 600837; MGI: 107430; HomoloGene: 433; GeneCards: GDNF; OMA:GDNF - orthologs
Orthologs
SpeciesHumanMouse
Entrez

2668

14573

Ensembl

ENSG00000168621

ENSMUSG00000022144

UniProt

P39905

P48540

RefSeq (mRNA)

NM_010275
NM_001301332
NM_001301333
NM_001301357

RefSeq (protein)

NP_000505
NP_001177397
NP_001177398
NP_001265027
NP_954701

NP_001288261
NP_001288262
NP_001288286
NP_034405

Location (UCSC)Chr 5: 37.81 – 37.84 MbChr 15: 7.84 – 7.87 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Glial cell line-derived neurotrophic factor (GDNF) is a protein that, in humans, is encoded by the GDNF gene.[5] GDNF is a small protein that potently promotes the survival of many types of neurons.[6] It signals through GFRα receptors, particularly GFRα1. It is also responsible for the determination of spermatogonia into primary spermatocytes, i.e. it is received by RET proto-oncogene (RET) and by forming gradient with SCF it divides the spermatogonia into two cells. As the result there is retention of spermatogonia and formation of spermatocyte.[7][full citation needed]

GDNF family of ligands (GFL)[edit]

GDNF was discovered in 1991,[8] and is the first member of the GDNF family of ligands (GFL) found.

Function[edit]

GDNF is highly distributed throughout both the peripheral and central nervous system. It can be secreted by astrocytes, oligodendrocytes, Schwann cells, motor neurons, and skeletal muscle during the development and growth of neurons and other peripheral cells.[9]

The GDNF gene encodes a highly conserved neurotrophic factor. The recombinant form of this protein was shown to promote the survival and differentiation of dopaminergic neurons in culture, and was able to prevent apoptosis of motor neurons induced by axotomy. GDNF is synthesized as a 211 amino acid-long protein precursor, pro-GDNF.[9] The pre-sequence leads the protein to the endoplasmic reticulum for secretion. While secretion takes place, the protein precursor folds via a sulfide-sulfide bond and dimerizes. The protein then is modified by N-linked glycosylation during packaging and preparation in the Golgi apparatus. Finally, the protein precursor undergoes proteolysis due to a proteolytic consensus sequence in its C-terminus end and is cleaved to 134 amino acids.[9] Proteases that play a role in the proteolysis of pro-GDNF into mature GDNF include furin, PACE4, PC5A, PC5B, and PC7. Because multiple proteases can cleave the protein precursor, four different mature forms of GDNF can be produced.[9] The proteolytic processing of GDNF requires SorLA, a protein sorting receptor. SorLA does not bind to any other GFLs.[10] The mature form of the protein is a ligand for the product of the RET (rearranged during transfection) protooncogene. In addition to the transcript encoding GDNF, two additional alternative transcripts encoding distinct proteins, referred to as astrocyte-derived trophic factors, have also been described. Mutations in this gene may be associated with Hirschsprung's disease.[6]

GDNF has the ability to activate the ERK-1 and ERK-2 isoforms of MAP kinase in sympathetic neurons as well as P13K/AKT pathways via activation of its receptor tyrosine kinases.[11][12] It can also activate Src-family kinases through its GFRα1 receptor.[13]

The most prominent feature of GDNF is its ability to support the survival of dopaminergic[14] and motor neurons.[citation needed] It prevents apoptosis in motor neurons during development, decreases the overall loss of neurons during development, rescues cells from axotomy-induced death, and prevents chronic degeneration.[9]

These neuronal populations die in the course of Parkinson's disease and amyotrophic lateral sclerosis (ALS). GDNF also regulates kidney development and spermatogenesis, and has a powerful and rapid negative (ameliorating) effect on alcohol consumption.[15] GDNF also promotes hair follicle formation and cutaneous wound healing by targeting resident hair follicle stem cells (BSCs) in the bulge compartment.[16]

Structure[edit]

GDNF has a structure that is similar to TGF beta 2.[11] GDNF has two finger-like structures that interact with the GFRα1 receptor. N-linked glycosylation, which occurs during the secretion of pro-GDNF, takes place at the tip of one of the finger-like structures. The C-terminal of mature GDNF plays an important role in binding with both Ret and the GFRα1 receptor. The C-terminus forms a loop out of the interactions between cysteines Cys131, Cy133, Cys68, and Cys 72.[9]

Interactions[edit]

Glial cell line-derived neurotrophic factor has been shown to interact with GFRA1[9][17] and GDNF family receptor alpha 1. The activity of GDNF, as well as other GFLs, is mediated by RET receptor tyrosine kinase. In order for the receptor to modulate GDNF activity, GDNF must also be bound to GFRα1.[11] The intensity and duration of RET signaling can likewise be monitored by the GPI-anchor of GFRα1 by interacting with compartments of the cell membrane, such as lipid rafts or cleavage by phospholipases.[12] In cells that lack RET, some GDNF family ligand members also have the ability to be activated through the neural cell adhesion molecule (NCAM). GDNF can associate with NCAM through its GFRα1 GPI-anchor. The association between GDNF and NCAM results in the activation of cytoplasmic protein tyrosine kinases Fyn and FAK.[18]

Potential as therapeutics[edit]

GDNF has been investigated as a treatment for Parkinson's disease, though early research has not shown a significant effect.[8][19] Vitamin D potently induces GDNF expression.[20]

In 2012, the University of Bristol began a five-year clinical trial on Parkinson's sufferers, in which surgeons introduced a port into the skull of each of the 41 participants through which the drug could be delivered, in order to enable it to reach the damaged cells directly.[21] The results of the double-blind trial, where half the participants were randomly assigned to receive regular infusions of GDNF and the other half placebo infusions, did not show a statistically significant difference between the active treatment group and those who received placebo, but did confirm the effects on damaged brain cells.[22] The trial was funded by Parkinson's UK with support from The Cure Parkinson's Trust, whose founder, Tom Isaacs, was one of the participants.[23]

Neuropsychopharmacology[edit]

Administration of the African hallucinogen ibogaine potently increases GDNF expression in the ventral tegmental area, which is the mechanism behind the alkaloid's anti-addictive effect.[24] Rodent models for a non-psychedelic analogue of this compound show promise in promoting GDNF expression without the hallucinogenic or cardiotoxic effects well documented for ibogaine.[25]

There is evidence, that Gdnf is an alcohol-responsive gene upregulated during short-term alcohol intake but downregulated during withdrawal from excessive alcohol intake.[26] Specifically, one study showed that alcohol withdrawal alters the expression of Gdnf in addiction related brain areas like the ventral tegmental area (VTA) and the Nucleus Accumbens as well as DNA methylation of the Gdnf gene in rats.[27]

References[edit]

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000168621 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000022144 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Lin LF, Doherty DH, Lile JD, Bektesh S, Collins F (May 1993). "GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons". Science. 260 (5111): 1130–2. Bibcode:1993Sci...260.1130L. doi:10.1126/science.8493557. PMID 8493557.
  6. ^ a b "Entrez Gene: GDNF glial cell derived neurotrophic factor". Archived from the original on 2010-03-07. Retrieved 2017-08-31.
  7. ^ Scott F. Gilbert
  8. ^ a b Vastag B (August 2010). "Biotechnology: Crossing the barrier". Nature. 466 (7309): 916–8. doi:10.1038/466916a. PMID 20725015.
  9. ^ a b c d e f g Cintrón-Colón AF, Almeida-Alves G, Boynton AM, Spitsbergen JM (October 2020). "GDNF synthesis, signaling, and retrograde transport in motor neurons". Cell and Tissue Research. 382 (1): 47–56. doi:10.1007/s00441-020-03287-6. PMC 7529617. PMID 32897420.
  10. ^ Glerup S, Lume M, Olsen D, Nyengaard JR, Vaegter CB, Gustafsen C, et al. (January 2013). "SorLA controls neurotrophic activity by sorting of GDNF and its receptors GFRα1 and RET". Cell Reports. 3 (1): 186–99. doi:10.1016/j.celrep.2012.12.011. PMID 23333276.
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Further reading[edit]

External links[edit]

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