{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T19:05:39Z","timestamp":1789758339796,"version":"4.0.1"},"reference-count":54,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2025,8,29]],"date-time":"2025-08-29T00:00:00Z","timestamp":1756425600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["FA 658\/3-1"],"award-info":[{"award-number":["FA 658\/3-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The aggregation of \u03b1-synuclein (\u03b1Syn) is a central feature of Parkinson\u2019s disease (PD) and other synucleinopathies. The efficient clearance of \u03b1Syn depends largely on the autophagy\u2013lysosomal pathway. Emerging genetic evidence highlights the role of pleckstrin homology and RUN domain-containing M1 protein (PLEKHM1), a critical regulator of autophagosome\u2013lysosome fusion, in the pathogenesis of multiple neurodegenerative diseases. This study investigates the possible effects of increased PLEKHM1 expression on \u03b1Syn pathology and neurodegeneration in mice. We utilized a mouse model of PD that is based on A53T-\u03b1Syn overexpression, achieved by the stereotactic injection of recombinant adeno-associated viral vectors (rAAV) into the substantia nigra. Additionally, this study explores the effect of PLEKHM1 overexpression on the autophagy\u2013lysosomal pathway under physiological conditions, using transgenic autophagy reporter mice. PLEKHM1 overexpression facilitated the \u03b1Syn-induced degeneration of dopaminergic somata in the substantia nigra and degeneration of dopaminergic axon terminals in the striatum. In concert with \u03b1Syn expression, PLEKHM1 also potentiated microglial activation. The extent of \u03b1Syn pathology, as reported by staining for phosphorylated \u03b1Syn, was not affected by PLEKHM1. Using RFP-EGFP-LC3 autophagy reporter mice, rAAV-mediated PLEKHM1 overexpression reduced lysosomal and autolysosomal area, increased LAMP1-LC3 colocalization, and decreased the autolysosome-to-autophagosome ratio. Concurrently, PLEKHM1 overexpression in both genotypes caused p62 accumulation, accompanied by reduced overlap with lysosomal and autophagosomal markers but increased colocalization with autolysosomal markers, indicating impaired cargo degradation during late-stage autophagy. Taken together, elevated PLEKHM1 levels exacerbate neurodegeneration in \u03b1Syn-overexpressing mice, possibly by impairing autophagic flux. Now, with in vivo evidence complementing genetic data, alterations in PLEKHM1 expression appear to compromise autophagy, potentially enhancing neuronal vulnerability to secondary insults like \u03b1Syn pathology.<\/jats:p>","DOI":"10.3390\/cells14171340","type":"journal-article","created":{"date-parts":[[2025,8,29]],"date-time":"2025-08-29T12:25:57Z","timestamp":1756470357000},"page":"1340","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["PLEKHM1 Overexpression Impairs Autophagy and Exacerbates Neurodegeneration in rAAV-\u03b1-Synuclein Mice"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-3114-916X","authenticated-orcid":false,"given":"Lennart","family":"H\u00f6fs","sequence":"first","affiliation":[{"name":"Department of Neurology, Faculty of Medicine, University Hospital Carl Gustav Carus, Technische Universit\u00e4t Dresden, 01307 Dresden, Germany"},{"name":"Deutsches Zentrum f\u00fcr Neurodegenerative Erkrankungen (DZNE), 01307 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-8332-2145","authenticated-orcid":false,"given":"David","family":"Gei\u00dfler-L\u00f6sch","sequence":"additional","affiliation":[{"name":"Department of Neurology, Faculty of Medicine, University Hospital Carl Gustav Carus, Technische Universit\u00e4t Dresden, 01307 Dresden, Germany"},{"name":"Deutsches Zentrum f\u00fcr Neurodegenerative Erkrankungen (DZNE), 01307 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2387-526X","authenticated-orcid":false,"given":"Bj\u00f6rn H.","family":"Falkenburger","sequence":"additional","affiliation":[{"name":"Department of Neurology, Faculty of Medicine, University Hospital Carl Gustav Carus, Technische Universit\u00e4t Dresden, 01307 Dresden, Germany"},{"name":"Deutsches Zentrum f\u00fcr Neurodegenerative Erkrankungen (DZNE), 01307 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1186\/s40035-020-00223-0","article-title":"Parkinson\u2019s Disease and Translational Research","volume":"9","author":"Dinter","year":"2020","journal-title":"Transl. 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