Glial cell line-derived neurotrophic factor

Glial cell-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 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]

GDNF
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2V5E, 3FUB, 4UX8
Identifiers
Aliases	GDNF, ATF1, ATF2, HFB1-HSCR3, glial cell derived neurotrophic factor, ATF
External IDs	OMIM: 600837 MGI: 107430 HomoloGene: 433 GeneCards: GDNF
Gene location (Human) Chr. Chromosome 5 (human)[1] Band 5p13.2 Start 37,812,677 bp[1] End 37,840,041 bp[1]
Gene location (Mouse) Chr. Chromosome 15 (mouse)[2] Band 15|15 A1 Start 7,810,846 bp[2] End 7,837,575 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • protein homodimerization activity • GO:0001948 protein binding • growth factor activity • receptor binding • Ras guanyl-nucleotide exchange factor activity • chemoattractant activity involved in axon guidance Cellular component • extracellular region • intracellular • extracellular Biological process • peristalsis • ureteric bud development • regulation of dopamine uptake involved in synaptic transmission • peripheral nervous system development • sympathetic nervous system development • organ induction • adult locomotory behavior • positive regulation of mesenchymal to epithelial transition involved in metanephros morphogenesis • regulation of stem cell differentiation • regulation of morphogenesis of a branching structure • mesenchymal to epithelial transition involved in metanephros morphogenesis • negative regulation of apoptotic process • nervous system development • positive regulation of monooxygenase activity • enteric nervous system development • mRNA stabilization • branching involved in ureteric bud morphogenesis • postganglionic parasympathetic fiber development • positive regulation of dopamine secretion • neural crest cell migration • postsynaptic membrane organization • positive regulation of cell proliferation • positive regulation of cell differentiation • positive regulation of ureteric bud formation • ureteric bud formation • regulation of gene expression • negative regulation of extrinsic apoptotic signaling pathway in absence of ligand • metanephros development • neuron projection development • signal transduction • positive regulation of transcription from RNA polymerase II promoter • MAPK cascade • axon guidance • negative regulation of neuron apoptotic process • positive regulation of branching involved in ureteric bud morphogenesis • regulation of receptor activity • dorsal spinal cord development • embryonic organ development • chemoattraction of axon • commissural neuron axon guidance • regulation of semaphorin-plexin signaling pathway Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	2668	14573
Ensembl	ENSG00000168621	ENSMUSG00000022144
UniProt	P39905	P48540
RefSeq (mRNA)	NM_000514 NM_001190468 NM_001190469 NM_001278098 NM_199231 NM_199234	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 Mb	Chr 15: 7.81 – 7.84 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

GDNF family of ligands (GFL)

GDNF was discovered in 1991,[7] 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.[8]

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 motorneurons. 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.[15]

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.[16] GDNF also promotes hair follicle formation and cutaneous wound healing by targeting resident hair follicle stem cells (BSCs) in the bulge compartment. [17]

Structure

GDNF has a structure that is similar to TGF beta 2.[18] 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][19] 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.[20] 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.[21] 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.[22]

Potential as therapeutics

GDNF has been investigated as a treatment for Parkinson's disease, though early research has not shown a significant effect.[7][23][24] Vitamin D potently induces GDNF expression.[25]

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.[26] 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.[27] 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.[28]

References

1. GRCh38: Ensembl release 89: ENSG00000168621 - Ensembl, May 2017
2. 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. "Entrez Gene: GDNF glial cell derived neurotrophic factor".
7. Vastag B (August 2010). "Biotechnology: Crossing the barrier". Nature. 466 (7309): 916–8. doi:10.1038/466916a. PMID 20725015.
8. 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. PMID 32897420.
9. 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. 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.
11. Kotzbauer 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. doi:10.1038/384467a0. PMID 8945474.
12. Ibáñez 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. doi:10.1016/j.nbd.2016.01.021. PMID 26829643.
13. Airaksinen MS, Saarma M (May 2002). "The GDNF family: signalling, biological functions and therapeutic value". Nature Reviews. Neuroscience. 3 (5): 383–94. doi:10.1038/nrn812. PMID 11988777.
14. Oo TF, Kholodilov N, Burke RE (June 2003). "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. doi:10.1523/JNEUROSCI.23-12-05141.2003. PMC 6741204. PMID 12832538.
15. 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. PMID 32897420.
16. Carnicella S, Kharazia V, Jeanblanc J, Janak PH, Ron D (June 2008). "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. Bibcode:2008PNAS..105.8114C. doi:10.1073/pnas.0711755105. PMC 2423415. PMID 18541917.
17. Lisse TS, Sharma M, Vishlaghi N, Pullagura SR, Braun RE (Jun 2020). "GDNF promotes hair formation and cutaneous wound healing by targeting bulge stem cells". NPJ Regenerative Medicine. 5 (13): 13. doi:10.1038/s41536-020-0098-z. PMC 7293257. PMID 32566252.
18. Kotzbauer 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. doi:10.1038/384467a0. PMID 8945474.
19. Cik M, Masure S, Lesage AS, Van Der Linden I, Van Gompel P, Pangalos MN, et al. (September 2000). "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. doi:10.1074/jbc.M000306200. PMID 10829012.
20. Kotzbauer 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. doi:10.1038/384467a0. PMID 8945474.
21. Ibáñez 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. doi:10.1016/j.nbd.2016.01.021. PMID 26829643.
22. Paratcha G, Ledda F, Ibáñez CF (June 2003). "The neural cell adhesion molecule NCAM is an alternative signaling receptor for GDNF family ligands". Cell. 113 (7): 867–79. doi:10.1016/s0092-8674(03)00435-5. PMID 12837245.
23. "Intermittent Bilateral Intraputamenal Treatment with GDNF". The Michael J. Fox Foundation for Parkinson's Research | Parkinson's Disease.
24. Brian Vastag. "Biotechnology: Crossing the barrier". Nature. Springer Nature. Retrieved 2019-03-27.
25. 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.
26. "The radical drug trial hoping for a miracle Parkinson's cure". BBC News. Retrieved 10 March 2019.
27. "GDNF clinical trial offers hope of restoring brain cells damaged in Parkinson's". Parkinsons UK. 27 February 2019. Retrieved 10 March 2019.
28. "Pioneering trial offers hope for restoring brain cells damaged in Parkinson's". University of Bristol. 2019-02-19.

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. PMID 9359036.
• 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. PMID 10917288.
• 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. PMID 7490108.
• Tomac A, Lindqvist E, Lin LF, Ogren SO, Young D, Hoffer BJ, Olson L (January 1995). "Protection and repair of the nigrostriatal dopaminergic system by GDNF in vivo". Nature. 373 (6512): 335–9. Bibcode:1995Natur.373..335T. doi:10.1038/373335a0. PMID 7830766. S2CID 4340992.
• 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. PMID 7830769. S2CID 2863274.
• 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. PMID 7867768. S2CID 37574956.
• 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.
• 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. PMID 8522325. S2CID 30960307.
• Gash DM, Zhang Z, Ovadia A, Cass WA, Yi A, Simmerman L, et al. (March 1996). "Functional recovery in parkinsonian monkeys treated with GDNF". Nature. 380 (6571): 252–5. Bibcode:1996Natur.380..252G. doi:10.1038/380252a0. PMID 8637574. S2CID 4313985.
• Jing S, Wen D, Yu Y, Holst PL, Luo Y, Fang M, et al. (June 1996). "GDNF-induced activation of the ret protein tyrosine kinase is mediated by GDNFR-alpha, a novel receptor for GDNF". Cell. 85 (7): 1113–24. doi:10.1016/S0092-8674(00)81311-2. PMID 8674117. S2CID 1724567.
• 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. PMID 8896568. S2CID 24350470.
• 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. PMID 8896569. S2CID 22375940.
• Ivanchuk SM, Myers SM, Eng C, Mulligan LM (December 1996). "De novo mutation of GDNF, ligand for the RET/GDNFR-alpha receptor complex, in Hirschsprung disease". Human Molecular Genetics. 5 (12): 2023–6. doi:10.1093/hmg/5.12.2023. PMID 8968758.
• 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. PMID 8988018.
• Bär KJ, Facer P, Williams NS, Tam PK, Anand P (April 1997). "Glial-derived neurotrophic factor in human adult and fetal intestine and in Hirschsprung's disease". Gastroenterology. 112 (4): 1381–5. doi:10.1016/S0016-5085(97)70154-9. PMID 9098026.
• Jing S, Yu Y, Fang M, Hu Z, Holst PL, Boone T, et al. (December 1997). "GFRalpha-2 and GFRalpha-3 are two new receptors for ligands of the GDNF family". The Journal of Biological Chemistry. 272 (52): 33111–7. doi:10.1074/jbc.272.52.33111. PMID 9407096.
• Eng C, Myers SM, Kogon MD, Sanicola M, Hession C, Cate RL, Mulligan LM (February 1998). "Genomic structure and chromosomal localization of the human GDNFR-alpha gene". Oncogene. 16 (5): 597–601. doi:10.1038/sj.onc.1201573. PMID 9482105.
• Amiel J, Salomon R, Attié T, Pelet A, Trang H, Mokhtari M, et al. (March 1998). "Mutations of the RET-GDNF signaling pathway in Ondine's curse". American Journal of Human Genetics. 62 (3): 715–7. doi:10.1086/301759. PMC 1376953. PMID 9497256.
• Yamaguchi Y, Wada T, Suzuki F, Takagi T, Hasegawa J, Handa H (August 1998). "Casein kinase II interacts with the bZIP domains of several transcription factors". Nucleic Acids Research. 26 (16): 3854–61. doi:10.1093/nar/26.16.3854. PMC 147779. PMID 9685505.
• Oo TF, Kholodilov N, Burke RE (June 2003). "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. doi:10.1523/JNEUROSCI.23-12-05141.2003. PMC 6741204. PMID 12832538.

External links

• Glial+Cell+Line-Derived+Neurotrophic+Factor at the US National Library of Medicine Medical Subject Headings (MeSH)