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Glial cell line-derived neurotrophic factor

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GDNF
Available structures
PDBOrtholog search:PDBeRCSB
Identifiers
AliasesGDNF,ATF1, ATF2, HFB1-HSCR3, glial cell derived neurotrophic factor, ATF
External IDsOMIM:600837;MGI:107430;HomoloGene:433;GeneCards:GDNF;OMA:GDNF - orthologs
Orthologs
SpeciesHumanMouse
Entrez

2668

14573

Ensembl

ENSG00000168621

ENSMUSG00000022144

UniProt

P39905

P48540

RefSeq (mRNA)

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 MbChr 15: 7.84 – 7.87 Mb
PubMedsearch[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Glial cell line-derived neurotrophic factor(GDNF) is aproteinthat, 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 family of ligands (GFL)

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GDNF was discovered in 1991,[8]and is the first member of theGDNF family of ligands(GFL) found.

Function

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GDNF is highly distributed throughout both the peripheral and central nervous system. It can be secreted byastrocytes,oligodendrocytes,Schwann cells,motor neurons,andskeletal muscleduring the development and growth of neurons and other peripheral cells.[9]

The GDNF gene encodes a highly conservedneurotrophic factor.The recombinant form of this protein was shown to promote the survival and differentiation ofdopaminergic neuronsin culture, and was able to preventapoptosisof motor neurons induced byaxotomy.GDNF is synthesized as a 211 amino acid-longprotein 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 byN-linked glycosylationduring packaging and preparation in theGolgi apparatus.Finally, theprotein precursorundergoesproteolysisdue to a proteolytic consensus sequence in itsC-terminusend and is cleaved to 134 amino acids.[9]Proteasesthat 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.[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 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.[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]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.[9]

These neuronal populations die in the course ofParkinson's diseaseandamyotrophic lateral sclerosis(ALS). GDNF also regulateskidneydevelopment andspermatogenesis,and has a powerful and rapid negative (ameliorating) effect onalcohol consumption.[15]GDNF also promoteshair follicleformation and cutaneouswound healingby targeting resident hair follicle stem cells (BSCs) in the bulge compartment.[16]

Structure

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GDNF has a structure that is similar toTGF beta 2.[11]GDNF has two finger-like structures that interact with theGFRα1receptor.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 bothRetand theGFRα1receptor. The C-terminus forms a loop out of the interactions betweencysteinesCys131, Cy133, Cys68, and Cys 72.[9]

Interactions

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Glial cell line-derived neurotrophic factor has been shown tointeractwithGFRA1[9][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.[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 byphospholipases.[12]In cells that lack RET, someGDNF family ligandmembers 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]

Potential as therapeutics

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GDNF has been investigated as a treatment for Parkinson's disease, though early research has not shown a significant effect.[8][19]Vitamin Dpotently induces GDNF expression.[20]

In 2012, theUniversity of Bristolbegan 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 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[23]) 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 plcmanufactured 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.[24]

Neuropsychopharmacology

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Administration of the African hallucinogenibogainepotently increases GDNF expression in theventral tegmental area,which is the mechanism behind the alkaloid's anti-addictive effect.[25]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.[26]

There is evidence, that Gdnf is an alcohol-responsivegeneupregulated during short-termalcoholintake but downregulated during withdrawal from excessive alcohol intake.[27]Specifically, one study showed that alcohol withdrawal alters the expression of Gdnf inaddictionrelated brain areas like theventral tegmental area(VTA) and theNucleus Accumbensas well asDNA methylationof the Gdnf gene in rats.[28]

References

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  1. ^abcGRCh38: Ensembl release 89: ENSG00000168621–Ensembl,May 2017
  2. ^abcGRCm38: 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.PMID8493557.
  6. ^ab"Entrez Gene: GDNF glial cell derived neurotrophic factor".Archivedfrom the original on 2010-03-07.Retrieved2017-08-31.
  7. ^Scott F. Gilbert
  8. ^abVastag B (August 2010)."Biotechnology: Crossing the barrier".Nature.466(7309): 916–8.doi:10.1038/466916a.PMID20725015.
  9. ^abcdefgCintrón-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.PMC7529617.PMID32897420.
  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.PMID23333276.
  11. ^abcKotzbauer PT, Lampe PA, Heuckeroth RO, Golden JP, Creedon DJ, Johnson EM, et al. (December 1996). "Neurturin, a relative of glial-cell-line-derived neurotrophic factor".Nature.384(6608): 467–70.Bibcode:1996Natur.384..467K.doi:10.1038/384467a0.PMID8945474.S2CID4238843.
  12. ^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.doi:10.1016/j.nbd.2016.01.021.PMID26829643.S2CID17588722.
  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.PMID11988777.S2CID2480120.
  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.PMC6741204.PMID12832538.
  15. ^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.PMC2423415.PMID18541917.
  16. ^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.PMC7293257.PMID32566252.
  17. ^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.PMID10829012.
  18. ^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.PMID12837245.
  19. ^"Intermittent Bilateral Intraputamenal Treatment with GDNF".The Michael J. Fox Foundation for Parkinson's Research | Parkinson's Disease.
  20. ^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.
  21. ^"The radical drug trial hoping for a miracle Parkinson's cure".BBC News.Archivedfrom the original on 10 March 2019.Retrieved10 March2019.
  22. ^"GDNF clinical trial offers hope of restoring brain cells damaged in Parkinson's".Parkinsons UK.27 February 2019.Archivedfrom the original on 27 March 2019.Retrieved10 March2019.
  23. ^"Pioneering trial offers hope for restoring brain cells damaged in Parkinson's".University of Bristol.2019-02-19.Archivedfrom the original on 2019-03-27.Retrieved2019-03-27.
  24. ^Whone A, Luz M, Boca M, Woolley M, Mooney L, Dharia S, et al. (March 2019)."Randomized trial of intermittent intraputamenal glial cell line-derived neurotrophic factor in Parkinson's disease".Brain.142(3): 512–525.doi:10.1093/brain/awz023.PMC6391602.PMID30808022.
  25. ^He DY, McGough NN, Ravindranathan A, Jeanblanc J, Logrip ML, Phamluong K, et al. (January 2005)."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.doi:10.1523/JNEUROSCI.3959-04.2005.PMC1193648.PMID15659598.
  26. ^Cameron LP, Tombari RJ, Lu J, Pell AJ, Hurley ZQ, Ehinger Y, et al. (January 2021)."A non-hallucinogenic psychedelic analogue with therapeutic potential".Nature.589(7842): 474–479.Bibcode:2021Natur.589..474C.doi:10.1038/s41586-020-3008-z.PMC7874389.PMID33299186.
  27. ^Barak S, Ahmadiantehrani S, Logrip ML, Ron D (May 2019)."GDNF and alcohol use disorder".Addiction Biology.24(3): 335–343.doi:10.1111/adb.12628.PMC6215739.PMID29726054.
  28. ^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.doi:10.1016/j.jpsychires.2019.10.020.PMID31710958.S2CID207964134.

Further reading

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