{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T02:58:24Z","timestamp":1792119504806,"version":"4.4.0"},"reference-count":188,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T00:00:00Z","timestamp":1777420800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Free Charity PhD studentship Fund","award":["285"],"award-info":[{"award-number":["285"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Neurodegenerative disorders, including Parkinson\u2019s disease (PD), are largely treated with symptomatic therapies, underscoring the need for strategies that target underlying disease mechanisms. Glucagon-like peptide-1 (GLP-1) and its receptor (GLP-1R), a class B G protein-coupled receptor best known for metabolic regulation, have attracted interest due to the increasing evidence of central nervous system (CNS) actions. This review synthesises mechanistic, preclinical, and clinical evidence examining GLP-1R signalling in PD and related neurodegenerative contexts. We integrate findings from cellular and animal models with early-phase clinical studies of GLP-1 receptor agonists (GLP-1RAs). Across experimental systems, GLP-1R activation engages conserved intracellular pathways\u2014cAMP\/PKA, PI3K\/Akt, and ERK\u2014that regulate mitochondrial function, oxidative stress, autophagy-lysosomal dynamics, and inflammatory signalling. In PD-relevant models, these pathways intersect with key pathogenic features, including \u03b1-synuclein accumulation, dopaminergic neuron vulnerability, and glial reactivity. Clinical studies to date demonstrate acceptable safety and tolerability, alongside biomarker evidence of central pathway engagement and variable effects on motor and non-motor outcomes. However, uncertainties remain regarding CNS target engagement, peripheral versus CNS mechanisms, and disease-stage dependence. Overall, the current evidence positions GLP-1R signalling as a biologically plausible therapeutic pathway in PD that warrants further mechanistic clarification and rigorous evaluation in ongoing and future clinical trials.<\/jats:p>","DOI":"10.3390\/cells15090804","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T13:32:22Z","timestamp":1777469542000},"page":"804","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["GLP-1 and Parkinson\u2019s Disease: A Comprehensive Review of Biology, Mechanisms and Efficacy"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8580-0629","authenticated-orcid":false,"given":"Roxana","family":"Mezabrovschi","sequence":"first","affiliation":[{"name":"Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8093-0723","authenticated-orcid":false,"given":"Matthew E.","family":"Gegg","sequence":"additional","affiliation":[{"name":"Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony H. V.","family":"Schapira","sequence":"additional","affiliation":[{"name":"Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,29]]},"reference":[{"key":"ref_1","first-page":"T31","article-title":"Central effects of GLP-1: New opportunities for treatments of neurodegenerative diseases","volume":"221","year":"2014","journal-title":"J. Endocrinol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1016\/j.drudis.2016.01.013","article-title":"The glucagon-like peptide 1 (GLP) receptor as a therapeutic target in Parkinson\u2019s disease: Mechanisms of action","volume":"21","author":"Athauda","year":"2016","journal-title":"Drug Discov. Today"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Kalinderi, K., Papaliagkas, V., and Fidani, L. (2024). 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