Biology:Glial cell line-derived neurotrophic factor

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example


Glial cell line-derived neurotrophic factor (GDNF) is a protein that, in humans, is encoded by the GDNF gene.[1] GDNF is a small protein that potently promotes the survival of many types of neurons.[2] 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.[3][full citation needed]

GDNF family of ligands (GFL)

GDNF was discovered in 1991,[4] and is the first member of the GDNF family of ligands (GFL) found.

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.[5]

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.[5] 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.[5] 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.[5] The proteolytic processing of GDNF requires SorLA, a protein sorting receptor. SorLA does not bind to any other GFLs.[6] 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.[2]

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.[7][8] It can also activate Src-family kinases through its GFRα1 receptor.[9]

The most prominent feature of GDNF is its ability to support the survival of dopaminergic[10] 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.[5]

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.[11] GDNF also promotes hair follicle formation and cutaneous wound healing by targeting resident hair follicle stem cells (BSCs) in the bulge compartment.[12]

Structure

GDNF has a structure that is similar to TGF beta 2.[7] 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.[5]

Interactions

Glial cell line-derived neurotrophic factor has been shown to interact with GFRA1[5][13] 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.[7] 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.[8] 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.[14]

Potential as therapeutics

GDNF has been investigated as a treatment for Parkinson's disease, though early research has not shown a significant effect.[4][15] Vitamin D potently induces GDNF expression.[16]

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.[17] 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.[18] 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.[19]

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.[20] 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.[21]

There is evidence, that Gdnf is an alcohol-responsive gene upregulated during short-term alcohol intake but downregulated during withdrawal from excessive alcohol intake.[22] 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.[23]

References

  1. ↑ "GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons". Science 260 (5111): 1130–2. May 1993. doi:10.1126/science.8493557. PMID 8493557. Bibcode: 1993Sci...260.1130L. 
  2. ↑ 2.0 2.1 "Entrez Gene: GDNF glial cell derived neurotrophic factor". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2668. 
  3. ↑ Scott F. Gilbert
  4. ↑ 4.0 4.1 "Biotechnology: Crossing the barrier". Nature 466 (7309): 916–8. August 2010. doi:10.1038/466916a. PMID 20725015. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 "GDNF synthesis, signaling, and retrograde transport in motor neurons". Cell and Tissue Research 382 (1): 47–56. October 2020. doi:10.1007/s00441-020-03287-6. PMID 32897420. 
  6. ↑ "SorLA controls neurotrophic activity by sorting of GDNF and its receptors GFRα1 and RET". Cell Reports 3 (1): 186–99. January 2013. doi:10.1016/j.celrep.2012.12.011. PMID 23333276. 
  7. ↑ 7.0 7.1 7.2 "Neurturin, a relative of glial-cell-line-derived neurotrophic factor". Nature 384 (6608): 467–70. December 1996. doi:10.1038/384467a0. PMID 8945474. Bibcode: 1996Natur.384..467K. 
  8. ↑ 8.0 8.1 "Biology of GDNF and its receptors - Relevance for disorders of the central nervous system". Neurobiology of Disease 97 (Pt B): 80–89. January 2017. doi:10.1016/j.nbd.2016.01.021. PMID 26829643. 
  9. ↑ "The GDNF family: signalling, biological functions and therapeutic value". Nature Reviews. Neuroscience 3 (5): 383–94. May 2002. doi:10.1038/nrn812. PMID 11988777. 
  10. ↑ "Regulation of natural cell death in dopaminergic neurons of the substantia nigra by striatal glial cell line-derived neurotrophic factor in vivo". The Journal of Neuroscience 23 (12): 5141–8. June 2003. doi:10.1523/JNEUROSCI.23-12-05141.2003. PMID 12832538. 
  11. ↑ "GDNF is a fast-acting potent inhibitor of alcohol consumption and relapse". Proceedings of the National Academy of Sciences of the United States of America 105 (23): 8114–9. June 2008. doi:10.1073/pnas.0711755105. PMID 18541917. Bibcode: 2008PNAS..105.8114C. 
  12. ↑ "GDNF promotes hair formation and cutaneous wound healing by targeting bulge stem cells". npj Regenerative Medicine 5 (13): 13. Jun 2020. doi:10.1038/s41536-020-0098-z. PMID 32566252. 
  13. ↑ "Binding of GDNF and neurturin to human GDNF family receptor alpha 1 and 2. Influence of cRET and cooperative interactions". The Journal of Biological Chemistry 275 (36): 27505–12. September 2000. doi:10.1074/jbc.M000306200. PMID 10829012. 
  14. ↑ "The neural cell adhesion molecule NCAM is an alternative signaling receptor for GDNF family ligands". Cell 113 (7): 867–79. June 2003. doi:10.1016/s0092-8674(03)00435-5. PMID 12837245. 
  15. ↑ "Intermittent Bilateral Intraputamenal Treatment with GDNF". https://www.michaeljfox.org/foundation/grant-detail.php?grant_id=664. 
  16. ↑ Eserian JK (July 2013). "Vitamin D as an effective treatment approach for drug abuse and addiction". Journal of Medical Hypotheses and Ideas 7 (2): 35–39. doi:10.1016/j.jmhi.2013.02.001. "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.". 
  17. ↑ "The radical drug trial hoping for a miracle Parkinson's cure". BBC News. https://www.bbc.co.uk/news/av/stories-47483307/the-radical-drug-trial-hoping-for-a-miracle-parkinson-s-cure. 
  18. ↑ "GDNF clinical trial offers hope of restoring brain cells damaged in Parkinson's". 27 February 2019. https://www.parkinsons.org.uk/news/gdnf-clinical-trial-offers-hope-restoring-brain-cells-damaged-parkinsons. 
  19. ↑ "Pioneering trial offers hope for restoring brain cells damaged in Parkinson's". 2019-02-19. https://www.bristol.ac.uk/news/2019/february/gdnf-trial.html. 
  20. ↑ "Glial cell line-derived neurotrophic factor mediates the desirable actions of the anti-addiction drug ibogaine against alcohol consumption". The Journal of Neuroscience 25 (3): 619–28. January 2005. doi:10.1523/JNEUROSCI.3959-04.2005. PMID 15659598. 
  21. ↑ "A non-hallucinogenic psychedelic analogue with therapeutic potential". Nature 589 (7842): 474–479. January 2021. doi:10.1038/s41586-020-3008-z. PMID 33299186. Bibcode: 2021Natur.589..474C. 
  22. ↑ "GDNF and alcohol use disorder". Addiction Biology 24 (3): 335–343. May 2019. doi:10.1111/adb.12628. PMID 29726054. 
  23. ↑ "Alcohol consumption alters Gdnf promoter methylation and expression in rats". Journal of Psychiatric Research 121: 1–9. February 2020. doi:10.1016/j.jpsychires.2019.10.020. PMID 31710958. 

Further reading

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