I.P. Pavlov Journal of Higher Nervous ActivityI.P. Pavlov Journal of Higher Nervous ActivityЖурнал высшей нервной деятельности им. И.П. Павлова0044-46773034-5316The Russian Academy of Sciences65206310.31857/S0044467724060049ОБЗОРЫ И ТЕОРЕТИЧЕСКИЕ СТАТЬИReview ArticleFundamental research and practical application of GDNF as a neuroprotective agent in neurodegenerative diseasesФундаментальные исследования и практическое использование нейропротекторных свойств GDNF при нейродегенеративных нарушенияхShamadykovaD. V.ШамадыковаД. В.
Russian Federation
djirgala04@gmail.comPavlovaG. V.ПавловаГ. В.
Russian Federation
lkorochkin@mail.ruInstitute of Higher Nervous Activity and Neurophysiology of the Russian Academy of Science (IHNA)ФГБУН «Институт высшей нервной деятельности и нейрофизиологии Российской академии наук» Минобрнауки РоссииBurdenko National Medical Research Center of NeurosurgeryФГАУ «Национальный медицинский исследовательский центр нейрохирургии им. акад. Н.Н. Бурденко» Минздрава РоссииI.M. Sechenov First Moscow State Medical University (MSMU)ФГАОУ ВО «Первый Московский государственный медицинский университет им. И.М. Сеченова» Минздрава России1112202474668770002022025Copyright ©; 2024, Russian Academy of SciencesCopyright ©; 2024, Российская академия наук2024Russian Academy of SciencesРоссийская академия наукhttps://innoscience.ru/0044-4677/article/view/652063

Glial cell line-derived neurotrophic factor (GDNF) is under extensive investigation as a therapeutic agent for treating age-related neurodegenerative diseases and traumatic neuronal injury. The compelling results from preclinical studies contrast with the disappointing outcomes of phase II clinical trials in Parkinson’s disease, highlighting the need for further fundamental research. Several hypotheses have been proposed to explain these discrepancies, including challenges with the delivery of high molecular weight drugs, GDNF’s high affinity for heparin and heparin-like molecules, which limits its biodistribution in the brain parenchyma, the use of protein forms differing from the native GDNF, and the existence of multiple isoforms of the protein. These issues underscore the necessity for further investigation into GDNF at the genetic, RNA, and protein levels. This review aims to consolidate the latest data on GDNF, address the challenges identified, and explore its potential for therapeutic application in human neurodegenerative diseases.

Глиальный нейротрофический фактор (GDNF) активно изучается в качестве терапевтического средства для лечения возрастных нейродегенеративных заболеваний, а также при травматической гибели нейронов. Интерес к дополнительному фундаментальному исследованию фактора обусловлен великолепным результатом в доклинических исследованиях и неудачами II фазы клинических исследований GDNF при болезни Паркинсона. Выдвинуты несколько предположений: проблемы, связанные с доставкой высокомолекулярных препаратов, высокая аффинность GDNF к гепарину и гепаринподобным молекулам, что препятствует биораспределению в паренхиме мозга, структура используемого белка, отличная от нативной формы, наличие различных изоформ белка. Все эти вопросы требовали очевидного дополнительного исследования GDNF как на уровне гена, так и на уровне РНК и белка. Данный обзор – попытка сфокусировать внимание на последних данных по GDNF, на разработках, направленных на решение возникших проблем и вероятностях его терапевтического применения при нейродегенеративных заболеваниях человека.

GDNFgene structureisoformsParkinson’s disease therapyneurodegenerative diseasesGDNFстроение генаизоформыболезнь ПаркинсонатерапияРоссийский научный фондRussian Science Foundation24-15-00157Adina T. Michael-Titus, Peter Shortland. The Nervous System, Third Edition. 2022. 233.Ai Y., Markesbery W., Zhang Z., Grondin R., Elseberry D., Gerhardt G.A., Gash D.M. Intraputamenal infusion of GDNF in aged rhesus monkeys: distribution and dopaminergic effects. J Comp Neurol. 2003. 461(2): 250–261.https://doi.org/10.1002/CNE.10689Airaksinen M.S., Saarma M. The GDNF family: Signalling, biological functions and therapeutic value. Nat Rev Neurosci. 2002. 3 (5): 383–394.https://doi.org/10.1038/nrn812Airaksinen M.S., Titievsky A., Saarma M. GDNF family neurotrophic factor signaling: Four masters, one servant. Mol Cell Neurosci. 1999. 13 (5): 313–325.https://doi.org/10.1006/mcne.1999.0754Ardashov O.V., Pavlova A.V., Mahato A.K., Sidorova Y., Morozova E.A., Korchagina D.V., Salnikov G.E., Genaev A.M., Patrusheva O.S., Li-Zhulanov N.S., Tolstikova T.G., Volcho K.P., Salakhutdinov N.F. A Novel Small Molecule Supports the Survival of Cultured Dopamine Neurons and May Restore the Dopaminergic Innervation of the Brain in the MPTP Mouse Model of Parkinson’s Disease. ACS Chem Neurosci. 2019. 10(10): 4337–4349.https://doi.org/10.1021/acschemneuro.9b00396Arenas E., Trupp M., Åkerud P., Ibáñez C.F. GDNF prevents degeneration and promotes the phenotype of brain noradrenergic neurons in vivo. Neuron. 1995. 15(6): 1465–1473.https://doi.org/10.1016/0896-6273(95)90024-1Baloh R.H., Enomoto H., Johnson E.M., Milbrandt J. The GDNF family ligands and receptors – implications for neural development. Curr Opin Neurobiol. 2000. 10(1): 103–110.https://doi.org/10.1016/S0959-4388(99)00048-3Baloh R.H., Johnson J.P., Avalos P., Allred P., Svendsen S., Gowing G., Roxas K., Wu A., Donahue B., Osborne S., Lawless G., Shelley B., Wheeler K., Prina C., Fine D., Kendra-Romito T., Stokes H., Manoukian V., Muthukumaran A., Garcia L., Bañuelos M.G., Godoy M., Bresee C., Yu H., Drazin D., Ross L., Naruse R., Babu H., Macklin E.A., Vo A., Elsayegh A., Tourtellotte W., Maya M., Burford M., Diaz F., Patil C.G., Lewis R.A., Svendsen C.N. Transplantation of human neural progenitor cells secreting GDNF into the spinal cord of patients with ALS: a phase 1/2a trial. Nat Med. 2022. 28(9): 1813–1822.https://doi.org/10.1038/S41591-022-01956-3Bartolini A., Cesare Mannelli L. Di, Ghelardini C. Analgesic and antineuropathic drugs acting through central cholinergic mechanisms. Recent Pat CNS Drug Discov. 2011. 6 (2): 119–140.https://doi.org/10.2174/157488911795933901Battaglia G., Molinaro G., Riozzi B., Storto M., Busceti C. L., Spinsanti P., Bucci D., Liberto V. Di, Mudò G., Corti C., Corsi M., Nicoletti F., Belluardo N., Bruno V. Activation of mGlu3 receptors stimulates the production of GDNF in striatal neurons. PLoS One. 2009. 4(8): e6591.https://doi.org/10.1371/journal.pone.0006591Baudet C., Mikaels A., Westphal H., Johansen J., Johansen T.E., Ernfors P. Positive and negative interactions of GDNF, NTN and ART in developing sensory neuron subpopulations, and their collaboration with neurotrophins. Development. 2000. 127(20): 4335–44.https://doi.org/10.1242/dev.127.20.4335Beck K.D., Valverde J., Alexi T., Poulsen K., Moffat B., Vandlen R.A., Rosenthal A., Hefti F. Mesencephalic dopaminergic neurons protected by gdnf from axotomy-induced degeneration in the adult brain. Nature. 1995. 373 (6512): 339–341.https://doi.org/10.1038/373339a0Bespalov M.M., Saarma M. GDNF family receptor complexes are emerging drug targets. Trends Pharmacol Sci. 2007. 28(2): 68–74.https://doi.org/10.1016/J.TIPS.2006.12.005Bespalov M.M., Sidorova Y.A., Tumova S., Ahonen-Bishopp A., Magalhães A.C., Kulesskiy E., Paveliev M., Rivera C., Rauvala H., Saarma M. Heparan sulfate proteoglycan syndecan-3 is a novel receptor for GDNF, neurturin, and artemin. Journal of Cell Biology. 2011. 192(1): 153–169.https://doi.org/10.1083/jcb.201009136Björklund A., Kirik D., Rosenblad C., Georgievska B., Lundberg C., Mandel R.J. Towards a neuroprotective gene therapy for Parkinson’s disease: use of adenovirus, AAV and lentivirus vectors for gene transfer of GDNF to the nigrostriatal system in the rat Parkinson model11Published on the World Wide Web on 10 October 2000. Brain Res. 2000. 886(1–2): 82–98.https://doi.org/10.1016/S0006-8993(00)02915-2Boger H.A., Middaugh L.D., Huang P., Zaman V., Smith A.C., Hoffer B.J., Tomac A.C., Granholm A.C. A partial GDNF depletion leads to earlier age-related deterioration of motor function and tyrosine hydroxylase expression in the substantia nigra. Exp Neurol. 2006. 202(2): 336–347.https://doi.org/10.1016/j.expneurol.2006.06.006Boger H.A., Middaugh L.D., Patrick K.S., Ramamoorthy S., Denehy E.D., Zhu H., Pacchioni A.M., Granholm A.C., McGinty J.F. Long-term consequences of methamphetamine exposure in young adults are exacerbated in glial cell line-derived neurotrophic factor heterozygous mice. Journal of Neuroscience. 2007. 27(33): 8816–8825.https://doi.org/10.1523/JNEUROSCI.1067-07.2007Bonafina A., Fontanet P.A., Paratcha G., Ledda F. GDNF/GFRα1 Complex Abrogates Self-Renewing Activity of Cortical Neural Precursors Inducing Their Differentiation. Stem Cell Reports. 2018. 10(3): 1000.https://doi.org/10.1016/J.STEMCR.2018.01.019Bourque M.J., Trudeau L.E. GDNF enhances the synaptic efficacy of dopaminergic neurons in culture. European Journal of Neuroscience. 2000. 12(9): 3172–3180.https://doi.org/10.1046/j.1460-9568.2000.00219.xBowenkamp K.E., Hoffman A.F., Gerhardt G.A., Henry M.A., Biddle P.T., Hoffer B.J., Granholm A.E. Glial cell line-derived neurotrophic factor supports survival of injured midbrain dopaminergic neurons. J Comp Neurol. 1995. 355(4): 479–489.https://doi.org/10.1002/CNE.903550402Bradley L.H., Fuqua J., Richardson A., Cholewo J.T., Ai Y., Kelps K.A., Glass J.D., He X., Zhang Z., Grondin R., Littrell O.M., Huettl P., Pomerleau F., Gash D.M., Gerhardt G.A. Dopamine Neuron Stimulating Actions of a GDNF Propeptide. PLoS One. 2010. 5(3): e9752.https://doi.org/10.1371/JOURNAL.PONE.0009752Bredell H., Smith J., Prins W., Görgens J., Zyl W. van. Expression of rotavirus VP6 protein: a comparison amongst Escherichia coli, Pichia pastoris and Hansenula polymorpha. FEMS Yeast Res. 2016. 16(2): fow001.https://doi.org/10.1093/FEMSYR/FOW001Burke R.E. Postnatal developmental programmed cell death in dopamine neurons. Annals of the New York Academy of Sciences. New York Academy of Sciences, 2003. 991:69–79.https://doi.org/10.1111/j.1749-6632.2003.tb07464.xCao J.P., Niu H.Y., Wang H.J., Huang X.G., Gao D.S. NF-κB p65/p52 plays a role in GDNF up-regulating Bcl-2 and Bcl-w expression in 6-OHDA-induced apoptosis of MN9D cell. International Journal of Neuroscience. 2013. 123(10): 705–710.https://doi.org/10.3109/00207454.2013.795149Chao M.V., Bothwell M. Neurotrophins: To cleave or not to cleave. Neuron. 2002. 33(1): 9–12.https://doi.org/10.1016/S0896-6273(01)00573-6Chen A.C.H., Eisch A.J., Sakai N., Takahashi M., Nestler E.J., Duman R.S. Regulation of GFRalpha-1 and GFRalpha-2 mRNAs in rat brain by electroconvulsive seizure. Synapse. 2001. 39(1): 42–50.https://doi.org/10.1002/1098-2396(20010101)39:1<42::aid-syn6>3.0.co;2-#Chermenina M., Schouten P., Nevalainen N., Johansson F., Orädd G., Strömberg I. GDNF is important for striatal organization and maintenance of dopamine neurons grown in the presence of the striatum. Neuroscience. 2014. 270: 1–11.https://doi.org/10.1016/j.neuroscience.2014.04.008Cintron-Colon A., Almeida-Alves G., Vangyseghem J., Spitsbergen J. GDNF to the rescue: GDNF delivery effects on motor neurons and nerves, and muscle re-innervation after peripheral nerve injuries. Neural Regen Res. 2022. 17(4): 748.https://doi.org/10.4103/1673-5374.322446Conway J.A., Kramer E.R. Is activation of GDNF/RET signaling the answer for successful treatment of Parkinson’s disease? A discussion of data from the culture dish to the clinic. Neural Regen Res. 2022. 17(7): 1462–1467.https://doi.org/10.4103/1673-5374.327330Creedon D.J., Tansey M.G., Baloh R.H., Osborne P.A., Lampe P.A., Fahrner T.J., Heuckeroth R.O., Milbrandt J., Johnson E.M. Neurturin shares receptors and signal transduction pathways with glial cell line-derived neurotrophic factor in sympathetic neurons. Proc Natl Acad Sci U S A. 1997. 94(13): 7018–7023.https://doi.org/10.1073/pnas.94.13.7018Croset A., Delafosse L., Gaudry J.P., Arod C., Glez L., Losberger C., Begue D., Krstanovic A., Robert F., Vilbois F., Chevalet L., Antonsson B. Differences in the glycosylation of recombinant proteins expressed in HEK and CHO cells. J Biotechnol. 2012. 161(3): 336–348.https://doi.org/10.1016/j.jbiotec.2012.06.038Dicou E. Multiple biological activities for two peptides derived from the nerve growth factor precursor. Biochem Biophys Res Commun. 2006. 347(3): 833–837.https://doi.org/10.1016/J.BBRC.2006.06.171Dicou E. High levels of the proNGF peptides LIP1 and LIP2 in the serum and synovial fluid of rheumatoid arthritis patients: evidence for two new cytokines. J Neuroimmunol. 2008. 194(1–2): 143–146.https://doi.org/10.1016/J.JNEUROIM.2007.11.002Dicou E., Pflug B., Magazin M., Lehy T., Djakiew D., Ferrara P., Nerrière V., Harvie D. Two peptides derived from the nerve growth factor precursor are biologically active. J Cell Biol. 1997. 136(2): 389–398.https://doi.org/10.1083/JCB.136.2.389Eggers R., Winter F. de, Tannemaat M.R., Malessy M.J.A., Verhaagen J. GDNF Gene Therapy to Repair the Injured Peripheral Nerve. Front Bioeng Biotechnol. 2020. 8: 583184.https://doi.org/10.3389/FBIOE.2020.583184/BIBTEXEigenbrot C., Gerber N. X-ray structure of glial cell-derived neurotrophic factor at 1.9 Å resolution and implications for receptor binding. Nat Struct Biol. 1997. 4(6): 435–438.https://doi.org/10.1038/nsb0697-435Enterría-Morales D., Rey N.L.G. Del, Blesa J., López-López I., Gallet S., Prevot V., López-Barneo J., D’Anglemont De Tassigny X. Molecular targets for endogenous glial cell line-derived neurotrophic factor modulation in striatal parvalbumin interneurons. Brain Commun. 2020. 2(2): fcaa105.https://doi.org/10.1093/BRAINCOMMS/FCAA105Flicek P., Ahmed I., Amode M.R., Barrell D., Beal K., Brent S., Carvalho-Silva D., Clapham P., Coates G., Fairley S., Fitzgerald S., Gil L., García-Girón C., Gordon L., Hourlier T., Hunt S., Juettemann T., Kähäri A. K., Keenan S., Komorowska M., Kulesha E., Longden I., Maurel T., McLaren W.M., Muffato M., Nag R., Overduin B., Pignatelli M., Pritchard B., Pritchard E., Riat H.S., Ritchie G.R.S., Ruffier M., Schuster M., Sheppard D., Sobral D., Taylor K., Thormann A., Trevanion S., White S., Wilder S.P., Aken B.L., Birney E., Cunningham F., Dunham I., Harrow J., Herrero J., Hubbard T.J.P., Johnson N., Kinsella R., Parker A., Spudich G., Yates A., Zadissa A., Searle S.M.J. Ensembl 2013. Nucleic Acids Res. 2013. 41(Database issue): D48https://doi.org/10.1093/NAR/GKS1236Fundin B.T., Mikaels Å., Westphal H., Ernfors P. A rapid and dynamic regulation of GDNF-family ligands and receptors correlate with the developmental dependency of cutaneous sensory innervation. Development. 1999. 126(12): 2597–2610.Fuqua J.L., Littrell O.M., Lundblad M., Turchan-Cholewo J., Abdelmoti L.G., Galperin E., Bradley L.H., Cass W.A., Gash D.M., Gerhardt G.A. Dynamic changes in dopamine neuron function after DNSP-11 treatment: Effects in vivo and increased ERK 1/2 phosphorylation in vitro. Peptides (N.Y.). 2014. 54: 1–8.https://doi.org/10.1016/j.peptides.2013.12.007Gash D.M., Zhang Z., Ai Y., Grondin R., Coffey R., Gerhardt G.A. Trophic factor distribution predicts functional recovery in parkinsonian monkeys. Ann Neurol. 2005. 58(2): 224–233.https://doi.org/10.1002/ANA.20549Gash D.M., Zhang Z., Cass W.A., Ovadia A., Simmerman L., Martin D., Russell D., Collins F., Hoffer B.J., Gerhardt G.A. Morphological and functional effects of intranigrally administered GDNF in normal rhesus monkeys. J Comp Neurol. 1995. 363(3): 345–358.https://doi.org/10.1002/CNE.903630302Gash D.M., Zhang Z., Ovadia A., Cass W.A., Yi A., Simmerman L., Russell D., Martin D., Lapchak P.A., Collins F., Hoffer B.J., Gerhardt G.A. Functional recovery in parkinsonian monkeys treated with GDNF. Nature. 1996. 380(6571): 252–255.https://doi.org/10.1038/380252a0Ghitza U.E., Zhai H., Wu P., Airavaara M., Shaham Y., Lu L. Role of BDNF and GDNF in drug reward and relapse: A review. Neurosci Biobehav Rev. 2010. 35 (2): 157–171.https://doi.org/10.1016/j.neubiorev.2009.11.009Gill S.S., Patel N.K., Hotton G.R., O’Sullivan K., McCarter R., Bunnage M., Brooks D.J., Svendsen C.N., Heywood P. Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease. Nat Med. 2003. 9(5): 589–595.https://doi.org/10.1038/nm850Goh J.B., Ng S.K. Impact of host cell line choice on glycan profile. Crit Rev Biotechnol. 2018. 38 (6): 851–867. https://doi.org/10.1080/07388551.2017.1416577Griffin W.C., Boger H.A., Granholm A.C., Middaugh L.D. Partial deletion of glial cell line-derived neurotrophic factor (GDNF) in mice: Effects on sucrose reward and striatal GDNF concentrations. Brain Res. 2006. 1068(1): 257–260.https://doi.org/10.1016/J.BRAINRES.2005.10.080Grimm L., Holinski-Feder E., Teodoridis J., Scheffer B., Schindelhauer D., Meitinger T., Ueffing M. Analysis of the human GDNF gene reveals an inducible promoter, three exons, a triplet repeat within the 3’-UTR and alternative splice products. Hum Mol Genet. 1998. 7(12): 1873–1886. https://doi.org/10.1093/hmg/7.12.1873Grondin R. Glial cell line-derived neurotrophic factor (GDNF): A drug candidate for the treatment of Parkinson’s disease. Journal of Neurology, Supplement. J Neurol. 1998. 245 (11 Suppl 3): 35–42.https://doi.org/10.1007/pl00007744Grondin R., Littrell O.M., Zhang Z., Ai Y., Huettl P., Pomerleau F., Quintero J.E., Andersen A.H., Stenslik M.J., Bradley L.H., Lemmon J., O’Neill M.J., Gash D.M., Gerhardt G.A. GDNF revisited: A novel mammalian cell-derived variant form of GDNF increases dopamine turnover and improves brain biodistribution. Neuropharmacology. 2019. 147: 28–36.https://doi.org/10.1016/j.neuropharm.2018.05.014Heiss J.D., Lungu C., Hammoud D.A., Herscovitch P., Ehrlich D.J., Argersinger D.P., Sinharay S., Scott G., Wu T., Federoff H.J., Zaghloul K.A., Hallett M., Lonser R.R., Bankiewicz K.S. Trial of magnetic resonance–guided putaminal gene therapy for advanced Parkinson’s disease. Movement Disorders. 2019. 34(7): 1073–1078.https://doi.org/10.1002/mds.27724Henderson C.E., Phillips H.S., Pollock R.A., Davies A.M., Lemeulle C., Armanini M., Simpson L.C., Moffet B., Vandlen R.A., Koliatsos V.E., Rosenthal A. GDNF: A potent survival factor for motoneurons present in peripheral nerve and muscle. Science (1979). 1994. 266(5187): 1062–1064.https://doi.org/10.1126/science.7973664Hoffer B.J., Hoffman A., Bowenkamp K., Huettl P., Hudson J., Martin D., Lin L.F.H., Gerhardt G.A. Glial cell line-derived neurotrophic factor reverses toxin-induced injury to midbrain dopaminergic neurons in vivo. Neurosci Lett. 1994. 182(1): 107–111.https://doi.org/10.1016/0304-3940(94)90218-6Ibáñez C.F. Jekyll-Hyde neurotrophins: the story of proNGF. Trends Neurosci. 2002. 25(6): 284–286. https://doi.org/10.1016/S0166-2236(02)02169-0Ibáñez C.F. Structure and physiology of the RET receptor tyrosine kinase. Cold Spring Harb Perspect Biol. 2013. 5(2):https://doi.org/10.1101/cshperspect.a009134Ilieva M., Nielsen J., Korshunova I., Gotfryd K., Bock E., Pankratova S., Michel T.M. Artemin and an artemin-derived peptide, artefin, induce neuronal survival, and differentiation through ret and NCAM. Front Mol Neurosci. 2019. 12: 47.https://doi.org/10.3389/FNMOL.2019.00047/FULLImmonen T., Alakuijala A., Hytönen M., Sainio K., Poteryaev D., Saarma M., Pasternack M., Sariola H. A proGDNF-related peptide BEP increases synaptic excitation in rat hippocampus. Exp Neurol. 2008. 210(2): 793–796.https://doi.org/10.1016/j.expneurol.2007.12.018Irala D., Bonafina A., Fontanet P.A., Alsina F.C., Paratcha G., Ledda F. The GDNF-GFRα1 complex promotes the development of hippocampal dendritic arbors and spines via NCAM. Development. 2016. 143(22): 4224–4235.https://doi.org/10.1242/DEV.140350Jain S., Golden U.P., Wozniak D., Pehek E., Johnson E.M., Milbrandt J. RET is dispensable for maintenance of midbrain dopaminergic neurons in adult mice. Journal of Neuroscience. 2006. 26(43): 11230–11238.https://doi.org/10.1523/JNEUROSCI.1876-06.2006Jing S., Wen D., Yu Y., Holst P.L., Luo Y., Fang M., Tamir R., Antonio L., Hu Z., Cupples R., Louis J.C., Hu S., Altrock B.W., Fox G.M. GDNF-induced activation of the Ret protein tyrosine kinase is mediated by GDNFR-α, a novel receptor for GDNF. Cell. 1996. 85(7): 1113–1124.https://doi.org/10.1016/S0092-8674(00)81311-2Kambey P.A., Kanwore K., Ayanlaja A.A., Nadeem I., Du Y.Z., Buberwa W., Liu W.Y., Gao D. Failure of Glial Cell-Line Derived Neurotrophic Factor (GDNF) in Clinical Trials Orchestrated By Reduced NR4A2 (NURR1) Transcription Factor in Parkinson’s Disease. A Systematic Review. Front Aging Neurosci. 2021. 13: 645583.https://doi.org/10.3389/FNAGI.2021.645583Kanning K.C., Kaplan A., Henderson C.E. Motor neuron diversity in development and disease. Annu Rev Neurosci. 2010. 33: 409–440.https://doi.org/10.1146/annurev.neuro.051508.135722Kelps K.A., Turchan-Cholewo J., Hascup E.R., Taylor T.L., Gash D.M., Gerhardt G.A., Bradley L.H. Evaluation of the physical and in vitro protective activity of three synthetic peptides derived from the pro- and mature GDNF sequence. Neuropeptides. 2011. 45(3): 213–218.https://doi.org/10.1016/j.npep.2011.03.003Kirik D., Georgievska B., Björklund A. Localized striatal delivery of GDNF as a treatment for Parkinson disease. Nat Neurosci. 2004. 7 (2): 105–110.https://doi.org/10.1038/nn1175Kokai L.E., Bourbeau D., Weber D., McAtee J., Marra K.G. Sustained growth factor delivery promotes axonal regeneration in long gap peripheral nerve repair. Tissue Eng Part A. 2011. 17(9–10): 1263–1275.https://doi.org/10.1089/ten.tea.2010.0507Kopra J., Vilenius C., Grealish S., Härma M.A., Varendi K., Lindholm J., Castrén E., Võikar V., Björklund A., Piepponen T.P., Saarma M., Andressoo J.O. GDNF is not required for catecholaminergic neuron survival in vivo. Nat Neurosci. 2015. 18 (3): 319–322.https://doi.org/10.1038/nn.3941Kramer E.R., Aron L., Ramakers G.M.J., Seitz S., Zhuang X., Beyer K., Smidt M.P., Klein R. Absence of Ret signaling in mice causes progressive and late degeneration of the nigrostriatal system. PLoS Biol. 2007. 5(3): 0616–0628.https://doi.org/10.1371/journal.pbio.0050039Kumar A., Kopra J., Varendi K., Porokuokka L.L., Panhelainen A., Kuure S., Marshall P., Karalija N., Härma M.A., Vilenius C., Lilleväli K., Tekko T., Mijatovic J., Pulkkinen N., Jakobson M., Jakobson M., Ola R., Palm E., Lindahl M., Strömberg I., Võikar V., Piepponen T.P., Saarma M., Andressoo J.O. GDNF Overexpression from the Native Locus Reveals its Role in the Nigrostriatal Dopaminergic System Function. PLoS Genet. 2015. 11(12): e1005710.https://doi.org/10.1371/journal.pgen.1005710Kust N., Panteleev D., Mertsalov I., Savchenko E., Rybalkina E., Revishchin A., Pavlova G. Availability of Pre- and Pro-regions of Transgenic GDNF Affects the Ability to Induce Axonal Sprout Growth. Mol Neurobiol. 2015. 51(3): 1195–1205.https://doi.org/10.1007/s12035-014-8792-8Lang A.E., Gill S., Patel N.K., Lozano A., Nutt J.G., Penn R., Brooks D.J., Hotton G., Moro E., Heywood P., Brodsky M.A., Burchiel K., Kelly P., Dalvi A., Scott B., Stacy M., Turner D., Wooten V.G.F., Elias W.J., Laws E.R., Dhawan V., Stoessl A.J., Matcham J., Coffey R.J., Traub M. Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease. Ann Neurol. 2006. 59(3): 459–466.https://doi.org/10.1002/ana.20737Lee R., Kermani P., Teng K.K., Hempstead B.L. Regulation of cell survival by secreted proneurotrophins. Science (1979). 2001. 294(5548): 1945–1948.https://doi.org/10.1126/science.1065057Leitner M.L., Molliver D.C., Osborne P.A., Vejsada R., Golden J.P., Lampe P.A., Kato A.C., Milbrandt J., Johnson E.M. Analysis of the retrograde transport of glial cell line-derived neurotrophic factor (GDNF), neurturin, and persephin suggests that in vivo signaling for the GDNF family is GFRα coreceptor-specific. Journal of Neuroscience. 1999. 19(21): 9322–9331.https://doi.org/10.1523/jneurosci.19-21-09322.1999Lin L.F.H., Doherty D.H., Lile J.D., Bektesh S., Collins F. GDNF: A glial cell line – Derived neurotrophic factor for midbrain dopaminergic neurons. Science (1979). 1993. 260(5111): 1130–1132.https://doi.org/10.1126/science.8493557Lindahl M., Poteryaev D., Yu L., Arumäe U., Timmusk T., Bongarzone I., Aiello A., Pierotti M.A., Airaksinen M.S., Saarma M. Human Glial Cell Line-derived Neurotrophic Factor Receptor α4 is the Receptor for Persephin and is Predominantly Expressed in Normal and Malignant Thyroid Medullary Cells. Journal of Biological Chemistry. 2001. 276(12): 9344–9351.https://doi.org/10.1074/jbc.M008279200Liu Q.R., Zhu M., Chen Q., Mustapic M., Kapogiannis D., Egan J.M. Novel Hominid-Specific IAPP Isoforms: Potential Biomarkers of Early Alzheimer’s Disease and Inhibitors of Amyloid Formation. Biomolecules. 2023. 13(1): 167.https://doi.org/10.3390/BIOM13010167Longo F.M., Massa S.M. Small-molecule modulation of neurotrophin receptors: a strategy for the treatment of neurological disease. Nat Rev Drug Discov. 2013. 12(7): 507–525.https://doi.org/10.1038/NRD4024Lonka-Nevalaita L., Lume M., Leppänen S., Jokitalo E., Peränen J., Saarma M. Characterization of the intracellular localization, processing, and secretion of two glial cell line-derived neurotrophic factor splice isoforms. Journal of Neuroscience. 2010. 30(34): 11403–11413.https://doi.org/10.1523/JNEUROSCI.5888-09.2010Love S., Plaha P., Patel N.K., Hotton G.R., Brooks D.J., Gill S.S. Glial cell line-derived neurotrophic factor induces neuronal sprouting in human brain. Nat Med. 2005. 11 (7): 703–704.https://doi.org/10.1038/nm0705-703Luz M., Whone A., Bassani N., Wyse R.K., Stebbins G.T., Mohr E. The Parkinson’s Disease Comprehensive Response (PDCORE): a composite approach integrating three standard outcome measures. Brain Commun. 2020. 2(2): fcaa046.https://doi.org/10.1093/braincomms/fcaa046Manié S., Santoro M., Fusco A., Billaud M. The RET receptor: Function in development and dysfunction in congenital malformation. Trends in Genetics. 2001. 17 (10): 580–589.https://doi.org/10.1016/S0168-9525(01)02420-9Marks W.J., Bartus R.T., Siffert J., Davis C.S., Lozano A., Boulis N., Vitek J., Stacy M., Turner D., Verhagen L., Bakay R., Watts R., Guthrie B., Jankovic J., Simpson R., Tagliati M., Alterman R., Stern M., Baltuch G., Starr P.A., Larson P.S., Ostrem J.L., Nutt J., Kieburtz K., Kordower J.H., Olanow C.W. Gene delivery of AAV2-neurturin for Parkinson’s disease: A double-blind, randomised, controlled trial. Lancet Neurol. 2010. 9(12): 1164–1172.https://doi.org/10.1016/S1474-4422(10)70254-4Marshall P. Finding an Optimal Level of GDNF Overexpression: Insights from Dopamine Cycling. Cell Mol Neurobiol. 2023. 43(7): 3179–3189.https://doi.org/10.1007/S10571-023-01375-ZMeka D.P., Müller-Rischart A.K., Nidadavolu P., Mohammadi B., Motori E., Ponna S.K., Aboutalebi H., Bassal M., Annamneedi A., Finckh B., Miesbauer M., Rotermund N., Lohr C., Tatzelt J., Winklhofer K.F., Kramer E.R. Parkin cooperates with GDNF/RET signaling to prevent dopaminergic neuron degeneration. Journal of Clinical Investigation. 2015. 125(5): 1873–1885.https://doi.org/10.1172/JCI79300Morrison P.F., Lonser R.R., Oldfield E.H. Convective delivery of glial cell line-derived neurotrophic factor in the human putamen. J Neurosurg. 2007. 107(1): 74–83.https://doi.org/10.3171/JNS-07/07/0074Nguyen Q.T., Parsadanian A.S., Snider W.D., Lichtman J.W. Hyperinnervation of neuromuscular junctions caused by GDNF overexpression in muscle. Science (1979). 1998. 279(5357): 1725–1729.https://doi.org/10.1126/science.279.5357.1725Nutt J.G., Burchiel K.J., Comella C.L., Jankovic J., Lang A.E., Laws E.R., Lozano A.M., Penn R.D., Simpson R.K., Stacy M., Wooten G.F., Johnston L., Lopez J., Harrigan M., Marciano F.F., Carter J.H., Stone C., Trugman J., Rost-Ruffner E., O’Brien C., McVicker J.H., Davis T.L., Charles D., Allen G., Weiner W., Landy H.J., Bronstein J., Koller W., Pahwa R., Wilkinson S., Siemers E.R., Wojcieszek J.M., Witt T., Tuite P.J., Ebbitt B.J., Maxwell R., Cravets M., Hilt D., Klein M., Lee D.R., Schultz B. Randomized, double-blind trial of glial cell line-derived neurotrophic factor (GDNF) in PD. Neurology. 2003. 60(1): 69–73.https://doi.org/10.1212/WNL.60.1.69Nykjaer A., Lee R., Teng K.K., Jansen P., Madsen P., Nielsen M.S., Jacobsen C., Kliemannel M., Schwarz E., Willnow T.E., Hempstead B.L., Petersen C.M. Sortilin is essential for proNGF-induced neuronal cell death. Nature. 2004. 427(6977): 843–848.https://doi.org/10.1038/nature02319Ohnaka M., Miki K., Gong Y.Y., Stevens R., Iwase T., Hackett S.F., Campochiaro P.A. Long-term expression of glial cell line-derived neurotrophic factor slows, but does not stop retinal degeneration in a model of retinitis pigmentosa. J Neurochem. 2012. 122(5): 1047–1053.https://doi.org/10.1111/j.1471-4159.2012.07842.xParatcha G., Ibáñez C.F. Lipid rafts and the control of neurotrophic factor signaling in the nervous system: Variations on a theme. Curr Opin Neurobiol. 2002. 12 (5): 542–549.https://doi.org/10.1016/S0959-4388(02)00363-XParatcha G., Ledda F. GDNF and GFRα: a versatile molecular complex for developing neurons. Trends Neurosci. 2008. 31(8): 384–391.https://doi.org/10.1016/j.tins.2008.05.003Paratcha G., Ledda F., Baars L., Coulpier M., Besset V., Anders J., Scott R., Ibáñez C.F. Released GFRα1 potentiates downstream signaling, neuronal survival, and differentiation via a novel mechanism of recruitment of c-Ret to lipid rafts. Neuron. 2001. 29(1): 171–184.https://doi.org/10.1016/S0896-6273(01)00188-XParatcha G., Ledda F., Ibáñez C.F. The neural cell adhesion molecule NCAM is an alternative signaling receptor for GDNF family ligands. Cell. 2003. 113(7): 867–879.https://doi.org/10.1016/S0092-8674(03)00435-5Pascual A., Hidalgo-Figueroa M., Piruat J.I., Pintado C.O., Gómez-Díaz R., López-Barneo J. Absolute requirement of GDNF for adult catecholaminergic neuron survival. Nat Neurosci. 2008. 11(7): 755–761.https://doi.org/10.1038/nn.2136Patel N.K., Pavese N., Javed S., Hotton G.R., Brooks D.J., Gill S.S. Benefits of putaminal GDNF infusion in Parkinson disease are maintained after GDNF cessation. Neurology. 2013. 81(13): 1176–1178.https://doi.org/10.1212/WNL.0b013e3182a55ea5Piccinini E., Kalkkinen N., Saarma M., Runeberg-Roos P. Glial cell line-derived neurotrophic factor: Characterization of mammalian posttranslational modifications. Ann Med. 2013. 45(1): 66–73.https://doi.org/10.3109/07853890.2012.663927Pichel J.G., Shen L., Sheng H.Z., Granholm A.C., Drago J., Grinberg A., Lee E.J., Sing Ping Huang, Saarma M., Hoffer B.J., Sariola H., Westphal H. Defects in enteric innervation and kidney development in mice lacking GDNF. Nature. 1996. 382(6586): 73–75.https://doi.org/10.1038/382073A0Piltonen M., Bespalov M.M., Ervasti D., Matilainen T., Sidorova Y.A., Rauvala H., Saarma M., Männistö P.T. Heparin-binding determinants of GDNF reduce its tissue distribution but are beneficial for the protection of nigral dopaminergic neurons. Exp Neurol. 2009. 219(2): 499–506.https://doi.org/10.1016/j.expneurol.2009.07.002Rattenholl A., Ruoppolo M., Flagiello A., Monti M., Vinci F., Marino G., Lilie H., Schwarz E., Rudolph R. Pro-sequence assisted folding and disulfide bond formation of human nerve growth factor. J Mol Biol. 2001. 305(3): 523–533.https://doi.org/10.1006/JMBI.2000.4295Revishchin A., Moiseenko L., Kust N., Bazhenova N., Teslia P., Panteleev D., Kovalzon V., Pavlova G. Effects of striatal transplantation of cells transfected with GDNF gene without pre- and pro-regions in mouse model of Parkinson’s disease. BMC Neurosci. 2016. 17(1): 34.https://doi.org/10.1186/s12868-016-0271-xRind H.B., Butowt R., Bartheld C.S. Von. Synaptic targeting of retrogradely transported trophic factors in motoneurons: Comparison of glial cell line-derived neurotrophic factor, brain-derived neurotrophic factor, and cardiotrophin-1 with tetanus toxin. Journal of Neuroscience. 2005. 25(3): 539–549.https://doi.org/10.1523/JNEUROSCI.4322-04.2005Rosenblad C., Kirik D., Björklund A. Sequential administration of GDNF into the substantia nigra and striatum promotes dopamine neuron survival and axonal sprouting but not striatal reinnervation or functional recovery in the partial 6-OHDA lesion model. Exp Neurol. 2000. 161(2): 503–516.https://doi.org/10.1006/EXNR.1999.7296Rossi J., Luukko K., Poteryaev D., Laurikainen A., Sun Y.F., Laakso T., Eerikäinen S., Tuominen R., Lakso M., Rauvala H., Arumäe U., Pasternack M., Saarma M., Airaksinen M.S. Retarded Growth and Deficits in the Enteric and Parasympathetic Nervous System in Mice Lacking GFRα2, a Functional Neurturin Receptor. Neuron. 1999. 22(2): 243–252.https://doi.org/10.1016/S0896-6273(00)81086-7Runeberg-Roos P., Piccinini E., Penttinen A.M., Mätlik K., Heikkinen H., Kuure S., Bespalov M.M., Peränen J., GareaRodríguez E., Fuchs E., Airavaara M., Kalkkinen N., Penn R., Saarma M. Developing therapeutically more efficient Neurturin variants for treatment of Parkinson’s disease. Neurobiol Dis. 2016. 96: 335–345.https://doi.org/10.1016/j.nbd.2016.07.008Salvatore M.F., Ai Y., Fischer B., Zhang A.M., Grondin R.C., Zhang Z., Gerhardt G.A., Gash D.M. Point source concentration of GDNF may explain failure of phase II clinical trial. Exp Neurol. 2006. 202(2): 497–505.https://doi.org/10.1016/j.expneurol.2006.07.015Sari Y. Huntington’s Disease: From Mutant Huntingtin Protein to Neurotrophic Factor Therapy. Int J Biomed Sci. 2011. 7(2): 89–100.Sariola H., Saarma M. GDNF and its receptors in the regulation of the ureteric branching. International Journal of Developmental Biology. 1999. 43 (5): 413–418.https://doi.org/10.1387/ijdb.10535317Sariola H., Saarma M. Novel functions and signalling pathways for GDNF. J Cell Sci. 2003. 116(19): 3855–3862.https://doi.org/10.1242/jcs.00786Sauer H., Rosenblad C., Björklund A. Glial cell line-derived neurotrophic factor but not transforming growth factor β3 prevents delayed degeneration of nigral dopaminergic neurons following striatal 6-hydroxydopamine lesion. Proc Natl Acad Sci U S A. 1995. 92(19): 8935–8939.https://doi.org/10.1073/pnas.92.19.8935Schmutzler B.S., Roy S., Pittman S.K., Meadows R.M., Hingtgen C.M. Ret-dependent and Ret-independent mechanisms of Gfl-induced sensitization. Mol Pain. 2011. 7:22.https://doi.org/10.1186/1744-8069-7-22Shamadykova D.V., Panteleev D.Y., Kust N.N., Savchenko E.A., Rybalkina E.Y., Revishchin A.V., Pavlova G.V. Neuroinductive properties of mGDNF depend on the producer, E. Coli or human cells. PLoS One. 2021. 16(10): e0258289.https://doi.org/10.1371/journal.pone.0258289Sherer T.B., Fiske B.K., Svendsen C.N., Lang A.E., Langston J.W. Crossroads in GDNF therapy for Parkinson’s disease. Movement Disorders. 2006. 21 (2): 136–141.https://doi.org/10.1002/mds.20861Sidorova Y.A., Saarma M. Small Molecules and Peptides Targeting Glial Cell Line-Derived Neurotrophic Factor Receptors for the Treatment of Neurodegeneration. International Journal of Molecular Sciences. 2020. 21(18): 6575.https://doi.org/10.3390/IJMS21186575Solius G., Panteleev D., Pustogarov N., Revishchin A., Poletaeva I., Pavlova G. Time course of transient expression of pre-α-pro-GDNF and pre-β-pro-GDNF transcripts, and mGDNF mRNA region in Krushinsky–Molodkina rat brain after audiogenic seizures. Epilepsy & Behavior. 2019. 96: 87–91.https://doi.org/10.1016/J.YEBEH.2019.03.007Suter U., J V Heymach J., Shooter E.M. Two conserved domains in the NGF propeptide are necessary and sufficient for the biosynthesis of correctly processed and biologically active NGF. EMBO J. 1991. 10(9): 2395.https://doi.org/10.1002/J.1460-2075.1991.TB07778.X.Suter-Crazzolara C., Unsicker K. GDNF is expressed in two forms in many tissues outside the CNS. Neuroreport. 1994. 5(18): 2486–2488.https://doi.org/10.1097/00001756-199412000-00020Suvanto P., Wartiovaara K., Lindahl M., Arumäe U., Moshnyakov M., Horelli-Kuitunen N., Airaksinen M.S., Palotie A., Sariola H., Saarma M. Cloning, mRNA distribution and chromosomal localisation of the gene for glial cell line-derived neurotrophic factor receptor β, a homologue to GDNFR-α. Hum Mol Genet. 1997. 6(8): 1267–1273.https://doi.org/10.1093/hmg/6.8.1267Takahashi M. The GDNF/RET signaling pathway and human diseases. Cytokine Growth Factor Rev. 2001. 12(4): 361–373.https://doi.org/10.1016/S1359-6101(01)00012-0Takahashi M., Ritz J., Cooper G.M. Activation of a novel human transforming gene, ret, by DNA rearrangement. Cell. 1985. 42(2): 581–588.https://doi.org/10.1016/0092-8674(85)90115-1Teng H.K., Teng K.K., Lee R., Wright S., Tevar S., Almeida R.D., Kermani P., Torkin R., Chen Z.Y., Lee F.S., Kraemer R.T., Nykjaer A., Hempstead B.L. ProBDNF induces neuronal apoptosis via activation of a receptor complex of p75NTR and sortilin. J Neurosci. 2005. 25(22): 5455–5463.https://doi.org/10.1523/JNEUROSCI.5123-04.2005Tomac A., Lindqvist E., Lin L.F.H., ögren S.O., Young D., Hoffer B.J., Olson L. Protection and repair of the nigrostriatal dopaminergic system by gdnf in vivo. Nature. 1995a. 373(6512): 335–339.https://doi.org/10.1038/373335a0Tomac A., Widenfalk J., Lin L.F.H., Kohno T., Ebendal T., Hoffer B.J., Olson L. Retrograde axonal transport of glial cell line-derived neurotrophic factor in the adult nigrostriatal system suggests a trophic role in the adult. Proc Natl Acad Sci U S A. 1995b. 92(18): 8274–8278.https://doi.org/10.1073/pnas.92.18.8274Trupp M., Rydén M., Jörnvall H., Funakoshi H., Timmusk T., Arenas E., Ibáñez C. F. Peripheral expression and biological activities of GDNF, a new neurotrophic factor for avian and mammalian peripheral neurons. Journal of Cell Biology. 1995. 130(1): 137–148.https://doi.org/10.1083/jcb.130.1.137Tsui C.C., Pierchala B.A. The differential axonal degradation of ret accounts for cell-type-specific function of glial cell line-derived neurotrophic factor as a retrograde survival factor. Journal of Neuroscience. 2010. 30(15): 5149–5158.https://doi.org/10.1523/JNEUROSCI.5246-09.2010Uchida S., Hara K., Kobayashi A., Otsuki K., Yamagata H., Hobara T., Suzuki T., Miyata N., Watanabe Y. Epigenetic status of Gdnf in the ventral striatum determines susceptibility and adaptation to daily stressful events. Neuron. 2011. 69(2): 359–372.https://doi.org/10.1016/j.neuron.2010.12.023Vastag B. Biotechnology: Crossing the barrier. Nature. 2010. 466(7309): 916–918.https://doi.org/10.1038/466916aVisanji N.P., Orsi A., Johnston T.H., Howson P.A., Dixon K., Callizot N., Brotchie J.M., Rees D.D. PYM50028, a novel, orally active, nonpeptide neurotrophic factor inducer, prevents and reverses neuronal damage induced by MPP + in mesencephalic neurons and by MPTP in a mouse model of Parkinson’s disease. The FASEB Journal. 2008. 22(7): 2488–2497.https://doi.org/10.1096/fj.07-095398Winkler C., Sauer H., Lee C.S., Björklund A. Short-term GDNF treatment provides long-term rescue of lesioned nigral dopaminergic neurons in a rat model of Parkinson’s disease. Journal of Neuroscience. 1996. 16(22): 7206–7215. https://doi.org/10.1523/jneurosci.16-22-07206.1996Worley D.S., Pisano J.M., Choi E.D., Walus L., Hession C.A., Cate R.L., Sanicola M., Birren S.J. Developmental regulation of GDNF response and receptor expression in the enteric nervous system. Development. 2000. 127(20): 4383–4393.https://doi.org/10.1242/DEV.127.20.4383Zhang Z., Miyoshi Y., Lapchak P.A., Collins F., Hilt D., Lebel C., Kryscio R., Gash D.M. Dose Response to Intraventricular Glial Cell Line-Derived Neurotrophic Factor Administration in Parkinsonian Monkeys. Journal of Pharmacology and Experimental Therapeutics. 1997. 282(3):1396-401.