Glial cell line-derived neurotrophic factor

GDNF was discovered in 1991,{{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 }} and is the first member of the GDNF family of ligands (GFL) found.

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.

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.{{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 }} 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. 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. The proteolytic processing of GDNF requires SorLA, a protein sorting receptor. SorLA does not bind to any other GFLs.{{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 | 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 }} 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.

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.{{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 }}{{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 }} It can also activate Src-family kinases through its GFRα1 receptor.{{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 }}

The most prominent feature of GDNF is its ability to support the survival of dopaminergic{{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 }} and motor neurons.{{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.

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.{{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 }} GDNF also promotes hair follicle formation and cutaneous wound healing by targeting resident hair follicle stem cells (BSCs) in the bulge compartment.{{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 }}

GDNF has a structure that is similar to TGF beta 2. 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.

Glial cell line-derived neurotrophic factor has been shown to interact with GFRA1{{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 = September 2000 | pmid = 10829012 | doi = 10.1074/jbc.M000306200 | doi-access = free }} 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. 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. 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.{{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 }}

GDNF has been investigated as a treatment for Parkinson's disease, though early research has not shown a significant effect.{{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}} Vitamin D potently induces GDNF expression.{{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}}

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.{{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}} 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.{{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}}

The study was funded by Parkinson’s UK (Grant J-1102), with support from The Cure Parkinson’s Trust (whose founder, Tom Isaacs, was one of the participants{{Cite web |date=2019-02-19 |title=Pioneering trial offers hope for restoring brain cells damaged in Parkinson's |url=https://www.bristol.ac.uk/news/2019/february/gdnf-trial.html |url-status=live |archive-url=https://web.archive.org/web/20190327162522/https://www.bristol.ac.uk/news/2019/february/gdnf-trial.html |archive-date=2019-03-27 |access-date=2019-03-27 |website=University of Bristol}}) and was sponsored by North Bristol NHS Trust. Study drug, additional project resources and supplementary funding was provided by MedGenesis Therapeutix Inc., who in turn received program funding support from the Michael J. Fox Foundation for Parkinson’s Research. Renishaw plc manufactured the CED device on behalf of North Bristol NHS Trust and provided additional technical and analytical support. The Gatsby Foundation provided a 3T MRI scanner.{{cite journal | vauthors = Whone A, Luz M, Boca M, Woolley M, Mooney L, Dharia S, Broadfoot J, Cronin D, Schroers C, Barua NU, Longpre L, Barclay CL, Boiko C, Johnson GA, Fibiger HC, Harrison R, Lewis O, Pritchard G, Howell M, Irving C, Johnson D, Kinch S, Marshall C, Lawrence AD, Blinder S, Sossi V, Stoessl AJ, Skinner P, Mohr E, Gill SS | title = Randomized trial of intermittent intraputamenal glial cell line-derived neurotrophic factor in Parkinson's disease | journal = Brain | volume = 142 | issue = 3 | pages = 512–525 | date = March 2019 | pmid = 30808022 | pmc = 6391602 | doi = 10.1093/brain/awz023 }}

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.{{cite journal | vauthors = He DY, McGough NN, Ravindranathan A, Jeanblanc J, Logrip ML, Phamluong K, Janak PH, Ron D | 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 }} 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.{{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 | 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 }}

There is evidence, that Gdnf is an alcohol-responsive gene upregulated during short-term alcohol intake but downregulated during withdrawal from excessive alcohol intake.{{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 }} 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.{{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 | 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 }}

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• {{MeshName|Glial+Cell+Line-Derived+Neurotrophic+Factor}}

{{PDB Gallery|geneid=2668}}

{{Neurotrophic factors}}

{{Growth factors}}

{{Growth factor receptor modulators}}

Category:Proteins

Category:TGFβ domain