{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T06:05:02Z","timestamp":1790661902812,"version":"4.1.0"},"reference-count":108,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Aging Neurosci."],"abstract":"<jats:p>\n                    Parkinson\u2019s disease (PD) is a debilitating neurodegenerative disorder with no available cure, underscoring the urgent need for novel therapeutics. This study employed the comprehensive bioinformatic analyses and the experimental models to investigate the potential of clemastine (CLE) for PD treatment. Bioinformatics identified 12 distinct cell subtypes and 577 differentially expressed genes in dopaminergic neurons (DaNs), along with 167 potential PD-relevant CLE targets. A significant correlation was found between Braak stage and autophagy-related gene expression in the substantia nigra. In MPP\n                    <jats:sup>+<\/jats:sup>\n                    -induced PC12 cell model, CLE treatment increased AMPK phosphorylation and decreased mTOR phosphorylation at Ser2448, suggesting the activation of AMPK and reduced mTOR activity, which was accompanied by the reduced levels of \u03b1-synuclein (\u03b1-syn) and p62, increased lysosomal (LAMP1) and autophagosomal (LC3) markers, and enhanced cell viability. CLE increased the LC3-II\/LC3-I ratio even in the presence of bafilomycin A1, indicating enhanced autophagosome synthesis. Conversely, the AMPK inhibitor dorsomorphin blocked CLE effects, restoring mTOR phosphorylation and \u03b1-syn levels. In the chronic MPTP-induced mouse model, CLE administration increased the phosphorylation of AMPK, increased the LC3-II\/LC3-I ratio, and decreased mTOR phosphorylation, p62, and \u03b1-syn levels. Immunofluorescence revealed the increased DaNs (tyrosine hydroxylase-positive) and LC3 puncta, alongside reduced the phosphorylated \u03b1-syn (p-S129). These cellular and molecular improvements correlated with the alleviation of both motor (rotarod test) and non-motor (fecal pellet output) deficits. Collectively, our findings suggest that CLE alleviates PD pathology by increasing AMPK phosphorylation and decreasing mTOR phosphorylation at Ser2448, suggesting the activation of AMPK pathway and reduced mTOR activity, thereby enhancing the autophagic flux by promoting both the synthesis and degradation of autophagosomes. Subsequently it facilitates the clearance of pathological \u03b1-syn, improves the neuronal survival, and ameliorates the behavioral symptoms. We propose CLE as a promising therapeutic candidate for PD via autophagy modulation.\n                  <\/jats:p>","DOI":"10.3389\/fnagi.2026.1915475","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T05:46:13Z","timestamp":1790660773000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Clemastine alleviates Parkinson\u2019s disease pathology by activating the AMPK\/mTOR pathway and enhancing autophagic flux"],"prefix":"10.3389","volume":"18","author":[{"given":"Ting","family":"Fan","sequence":"first","affiliation":[{"name":"School of Clinical Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang","place":["Jiangxi, China"]},{"name":"Department of Neurology, Jiangxi Provincial People\u2019s Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang","place":["Jiangxi, China"]},{"name":"Department of Neurology, National Regional Center for Neurological Diseases, Xiangya Hospital of Central South University Jiangxi Hospital, Nanchang","place":["Jiangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caihui","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Neurology, Jiangxi Provincial People\u2019s Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang","place":["Jiangxi, China"]},{"name":"Department of Neurology, National Regional Center for Neurological Diseases, Xiangya Hospital of Central South University Jiangxi Hospital, Nanchang","place":["Jiangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenzhi","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Neurology, Jiangxi Provincial People\u2019s Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang","place":["Jiangxi, China"]},{"name":"Department of Neurology, National Regional Center for Neurological Diseases, Xiangya Hospital of Central South University Jiangxi Hospital, Nanchang","place":["Jiangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Neurology, Jiangxi Provincial People\u2019s Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang","place":["Jiangxi, China"]},{"name":"Department of Neurology, National Regional Center for Neurological Diseases, Xiangya Hospital of Central South University Jiangxi Hospital, Nanchang","place":["Jiangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junling","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurology, National Regional Center for Neurological Diseases, Xiangya Hospital of Central South University Jiangxi Hospital, Nanchang","place":["Jiangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Cadres Health Care, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang","place":["Jiangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renshi","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Neurology, Jiangxi Provincial People\u2019s Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang","place":["Jiangxi, China"]},{"name":"Department of Neurology, National Regional Center for Neurological Diseases, Xiangya Hospital of Central South University Jiangxi Hospital, Nanchang","place":["Jiangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"5405","DOI":"10.3390\/ijms26115405","article-title":"\u03b1-Synuclein pathology in synucleinopathies: mechanisms.","volume":"26","author":"Arias-Carri\u00f3n","year":"2025","journal-title":"Int. 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