{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T21:28:49Z","timestamp":1781126929986,"version":"3.54.1"},"reference-count":195,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2021,10,28]],"date-time":"2021-10-28T00:00:00Z","timestamp":1635379200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Parkinson\u2019s disease (PD) is characterized by four pathognomonic hallmarks: (1) motor and non-motor deficits; (2) neuroinflammation and oxidative stress; (3) pathological aggregates of the \u03b1-synuclein (\u03b1-syn) protein; (4) neurodegeneration of the nigrostriatal system. Recent evidence sustains that the aggregation of pathological \u03b1-syn occurs in the early stages of the disease, becoming the first trigger of neuroinflammation and subsequent neurodegeneration. Thus, a therapeutic line aims at striking back \u03b1-synucleinopathy and neuroinflammation to impede neurodegeneration. Another therapeutic line is restoring the compromised dopaminergic system using neurotrophic factors, particularly the glial cell-derived neurotrophic factor (GDNF). Preclinical studies with GDNF have provided encouraging results but often lack evaluation of anti-\u03b1-syn and anti-inflammatory effects. In contrast, clinical trials have yielded imprecise results and have reported the emergence of severe side effects. Here, we analyze the discrepancy between preclinical and clinical outcomes, review the mechanisms of the aggregation of pathological \u03b1-syn, including neuroinflammation, and evaluate the neurorestorative properties of GDNF, emphasizing its anti-\u03b1-syn and anti-inflammatory effects in preclinical and clinical trials.<\/jats:p>","DOI":"10.3390\/ijms222111702","type":"journal-article","created":{"date-parts":[[2021,10,28]],"date-time":"2021-10-28T23:51:36Z","timestamp":1635465096000},"page":"11702","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Mechanistic Insight from Preclinical Models of Parkinson\u2019s Disease Could Help Redirect Clinical Trial Efforts in GDNF Therapy"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8321-0705","authenticated-orcid":false,"given":"Karen M.","family":"Delgado-Minjares","sequence":"first","affiliation":[{"name":"Centro de Investigaci\u00f3n y de Estudios Avanzados del Instituto Polit\u00e9cnico Nacional, Departamento de Fisiolog\u00eda, Biof\u00edsica y Neurociencias, Av. Instituto Polit\u00e9cnico Nacional No. 2508, Ciudad de M\u00e9xico 07360, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Martinez-Fong","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n y de Estudios Avanzados del Instituto Polit\u00e9cnico Nacional, Departamento de Fisiolog\u00eda, Biof\u00edsica y Neurociencias, Av. Instituto Polit\u00e9cnico Nacional No. 2508, Ciudad de M\u00e9xico 07360, Mexico"},{"name":"Programa de Doctorado en Nanociencias y Nanotecnolog\u00eda, Centro de Investigaci\u00f3n y de Estudios Avanzados del Instituto Polit\u00e9cnico Nacional, Av. Instituto Polit\u00e9cnico Nacional No. 2508, Ciudad de M\u00e9xico 07360, Mexico"},{"name":"Nanoparticle Therapy Institute 404 Avenida Monte Blanco Aguascalientes, Aguascalientes 20120, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irma A.","family":"Mart\u00ednez-D\u00e1vila","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n y de Estudios Avanzados del Instituto Polit\u00e9cnico Nacional, Departamento de Fisiolog\u00eda, Biof\u00edsica y Neurociencias, Av. Instituto Polit\u00e9cnico Nacional No. 2508, Ciudad de M\u00e9xico 07360, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecilia","family":"Ba\u00f1uelos","sequence":"additional","affiliation":[{"name":"Coordinaci\u00f3n General de Programas de Posgrado Multidisciplinarios, Programa de Doctorado Transdisciplinario en Desarrollo Cient\u00edfico y Tecnol\u00f3gico para la Sociedad, Centro de Investigaci\u00f3n y de Estudios Avanzados del Instituto Polit\u00e9cnico Nacional, Av. Instituto Polit\u00e9cnico Nacional No. 2508, Ciudad de M\u00e9xico 07360, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. E.","family":"Gutierrez-Castillo","sequence":"additional","affiliation":[{"name":"Centro Interdisciplinario de Investigaciones y Estudios sobre Medio Ambiente y Desarrollo, Departamento de Biociencias e Ingenier\u00eda, Instituto Polit\u00e9cnico Nacional, 30 de Junio de 1520 s\/n, Ciudad de M\u00e9xico 07340, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V\u00edctor Manuel","family":"Blanco-Alvarez","sequence":"additional","affiliation":[{"name":"Facultad de Medicina, Benem\u00e9rita Universidad Aut\u00f3noma de Puebla, 13 Sur 2702, Puebla 72420, Mexico"},{"name":"Facultad de Enfermer\u00eda, Benem\u00e9rita Universidad Aut\u00f3noma de Puebla, Av. 25 Poniente 1304, Los Volcanes, Puebla 72410, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria-del-Carmen","family":"Cardenas-Aguayo","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular Reprogramming, Departamento de Fisiolog\u00eda, Facultad de Medicina, UNAM. Av. Universidad No. 3000, Ciudad de M\u00e9xico 04510, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6927-913X","authenticated-orcid":false,"given":"Jos\u00e9","family":"Luna-Mu\u00f1oz","sequence":"additional","affiliation":[{"name":"National Dementia BioBank, Ciencias Biol\u00f3gicas, Facultad de Estudios Superiores Cuautitl\u00e1n, Universidad Nacional Aut\u00f3noma de M\u00e9xico, M\u00e9xico City 53150, Mexico"},{"name":"Banco Nacional de Cerebros, Universidad Nacional Pedro Henr\u00edquez Ure\u00f1a, Santo Domingo 1423, Dominican Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1983-0608","authenticated-orcid":false,"given":"Mar","family":"Pacheco-Herrero","sequence":"additional","affiliation":[{"name":"Neuroscience Research Laboratory, Faculty of Health Sciences, Pontificia Universidad Cat\u00f3lica Madre y Maestra, Santiago de los Caballeros 51000, Dominican Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5013-3608","authenticated-orcid":false,"given":"Luis O.","family":"Soto-Rojas","sequence":"additional","affiliation":[{"name":"Facultad de Estudios Superiores Iztacala, UNAM, Mexico City 54090, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.1007\/s43440-020-00120-3","article-title":"Neurotrophic factors for disease-modifying treatments of Parkinson\u2019s disease: Gaps between basic science and clinical studies","volume":"72","author":"Chmielarz","year":"2020","journal-title":"Pharmacol. 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