Glial cell line-derived neurotrophic factor (GDNF) is a
protein that, in humans, is encoded by the GDNFgene.[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]
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]
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
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
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
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]
^
abcKotzbauer PT, Lampe PA, Heuckeroth RO, Golden JP, Creedon DJ, Johnson EM, Milbrandt J (December 1996). "Neurturin, a relative of glial-cell-line-derived neurotrophic factor". Nature. 384 (6608): 467–70.
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^
abIbáñez CF, Andressoo JO (January 2017). "Biology of GDNF and its receptors - Relevance for disorders of the central nervous system". Neurobiology of Disease. 97 (Pt B): 80–89.
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^Airaksinen MS, Saarma M (May 2002). "The GDNF family: signalling, biological functions and therapeutic value". Nature Reviews. Neuroscience. 3 (5): 383–94.
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^Maier HB, Neyazi M, Neyazi A, Hillemacher T, Pathak H, Rhein M, et al. (February 2020). "Alcohol consumption alters Gdnf promoter methylation and expression in rats". Journal of Psychiatric Research. 121: 1–9.
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Further reading
Hofstra RM, Osinga J, Buys CH (1998). "Mutations in Hirschsprung disease: when does a mutation contribute to the phenotype". European Journal of Human Genetics. 5 (4): 180–5.
doi:
10.1159/000484760.
PMID9359036.
Martucciello G, Ceccherini I, Lerone M, Jasonni V (July 2000). "Pathogenesis of Hirschsprung's disease". Journal of Pediatric Surgery. 35 (7): 1017–25.
doi:
10.1053/jpsu.2000.7763.
PMID10917288.
Schindelhauer D, Schuffenhauer S, Gasser T, Steinkasserer A, Meitinger T (August 1995). "The gene coding for glial cell line derived neurotrophic factor (GDNF) maps to chromosome 5p12-p13.1". Genomics. 28 (3): 605–7.
doi:
10.1006/geno.1995.1202.
PMID7490108.
Oppenheim RW, Houenou LJ, Johnson JE, Lin LF, Li L, Lo AC, et al. (January 1995). "Developing motor neurons rescued from programmed and axotomy-induced cell death by GDNF". Nature. 373 (6512): 344–6.
Bibcode:
1995Natur.373..344O.
doi:
10.1038/373344a0.
PMID7830769.
S2CID2863274.
Schaar DG, Sieber BA, Sherwood AC, Dean D, Mendoza G, Ramakrishnan L, et al. (December 1994). "Multiple astrocyte transcripts encode nigral trophic factors in rat and human". Experimental Neurology. 130 (2): 387–93.
doi:
10.1006/exnr.1994.1218.
PMID7867768.
S2CID37574956.
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.
PMID8493557.
Bermingham N, Hillermann R, Gilmour F, Martin JE, Fisher EM (December 1995). "Human glial cell line-derived neurotrophic factor (GDNF) maps to chromosome 5". Human Genetics. 96 (6): 671–3.
doi:
10.1007/BF00210297.
PMID8522325.
S2CID30960307.
Angrist M, Bolk S, Halushka M, Lapchak PA, Chakravarti A (November 1996). "Germline mutations in glial cell line-derived neurotrophic factor (GDNF) and RET in a Hirschsprung disease patient". Nature Genetics. 14 (3): 341–4.
doi:
10.1038/ng1196-341.
PMID8896568.
S2CID24350470.
Salomon R, Attié T, Pelet A, Bidaud C, Eng C, Amiel J, et al. (November 1996). "Germline mutations of the RET ligand GDNF are not sufficient to cause Hirschsprung disease". Nature Genetics. 14 (3): 345–7.
doi:
10.1038/ng1196-345.
PMID8896569.
S2CID22375940.
Haniu M, Hui J, Young Y, Le J, Katta V, Lee R, et al. (December 1996). "Glial cell line-derived neurotrophic factor: selective reduction of the intermolecular disulfide linkage and characterization of its disulfide structure". Biochemistry. 35 (51): 16799–805.
doi:
10.1021/bi9605550.
PMID8988018.