Glial cell line-derived neurotrophic factor (GDNF) is aprotein that, in humans, is encoded by theGDNFgene.[5] GDNF is a small protein that potently promotes the survival of many types ofneurons.[6] It signals throughGFRα receptors, particularlyGFRα1.It is also responsible for the determination of spermatogonia into primary spermatocytes, i.e. it is received byRET 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 has a structure that is similar toTGF beta 2.[9] GDNF has two finger-like structures that interact with theGFRα1 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 bothRet and theGFRα1 receptor. The C-terminus forms a loop out of the interactions betweencysteines Cys131, Cy133, Cys68, and Cys 72.[10]
The GDNF gene encodes a highly conservedneurotrophic factor. The recombinant form of this protein was shown to promote the survival and differentiation ofdopaminergic neurons in culture, and was able to preventapoptosis of motor neurons induced byaxotomy. GDNF is synthesized as a 211 amino acid-longprotein precursor, pro-GDNF.[10] 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 byN-linked glycosylation during packaging and preparation in theGolgi apparatus. Finally, theprotein precursor undergoesproteolysis due to a proteolytic consensus sequence in itsC-terminus end and is cleaved to 134 amino acids.[10]Proteases that play a role in the proteolysis of pro-GDNF into mature GDNF includefurin, PACE4, PC5A, PC5B, and PC7. Because multiple proteases can cleave the protein precursor, four different mature forms of GDNF can be produced.[10] The proteolytic processing of GDNF requires SorLA, a protein sorting receptor. SorLA does not bind to any other GFLs.[11] The mature form of the protein is a ligand for the product of theRET (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 withHirschsprung'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 itsreceptor tyrosine kinases.[9][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] andmotor 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.[10]
Glial cell line-derived neurotrophic factor has been shown tointeract withGFRA1[10][17] andGDNF 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.[9] 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 byphospholipases.[12] In cells that lack RET, someGDNF family ligand members also have the ability to be activated through theneural 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]
Administration of the African hallucinogenibogaine potently increases GDNF expression in theventral tegmental area, which is the mechanism behind the alkaloid's anti-addictive effect.[19] 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.[20]
There is evidence, that Gdnf is an alcohol-responsivegene upregulated during short-termalcohol intake but downregulated during withdrawal from excessive alcohol intake.[21] Specifically, one study showed that alcohol withdrawal alters the expression of Gdnf inaddiction related brain areas like theventral tegmental area (VTA) and theNucleus Accumbens as well asDNA methylation of the Gdnf gene in rats.[22]
GDNF has been investigated as a treatment for Parkinson's disease, though early research did not show a significant effect.[8][23]Vitamin D potently induces GDNF expression.[24]
In 2012, theUniversity 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.[25] 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.[26]
The study was funded byParkinson’s UK (Grant J-1102), with support from The Cure Parkinson’s Trust (whose founder,Tom Isaacs, was one of the participants[27]) and was sponsored byNorth 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 theMichael 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.[28]
More recently, gene therapy approaches have been proposed as delivery mechanism for GDNF into the putamen for cases of mild and moderate stage Parkinson's disease.[29] A Phase 1b clinical trial investigating GDNF delivered via AAV2 (adeno-associated virus serotype 2), specifically AB-1005 (also known as AAV2-GDNF), started in 2020 and showed promising results, focusing on safety and preliminary efficacy.[30] A Phase 2 clinical trial called REGENERATE-PD started recruiting a target of 87 participants with moderate Parkinson's disease in 2024 and is expected to complete in 2027.[31]
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