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The heterotrimeric enzyme protein phosphatase 2A (PP2A), and specifically its B55\u03b1 containing isoform, which dephosphorylates phospho-S129-\u03b1-Syn, is regulated through methylation of its catalytic C subunit, a process that is controlled by the opposing activities of leucine carboxyl methyltransferase 1 (LCMT-1) and protein phosphatase methylesterase 1 (PME-1). Postmortem studies show decreased LCMT-1 and increased PME-1 levels in PD and DLB brains, leading to reduced PP2A activity and \u03b1-Syn hyperphosphorylation. To investigate the pathophysiological relevance of this regulatory axis, we employed genetically modified mice in two models of synucleinopathy, transgenic animals and intrastriatal \u03b1-Syn preformed fibrils (PFF) injections. A battery of behavioral tests was conducted to assess motor and cognitive function, followed by brain analyses quantifying phosphorylated \u03b1-Syn aggregates, neuronal toxicity, and neuroinflammatory responses, thereby evaluating how modulation of this axis influences \u03b1-Syn pathology. Overexpression of PME-1 in forebrain neurons exacerbated \u03b1-Syn pathology, characterized by increased Ser129 phosphorylation and aggregation, as well as neurodegeneration and neuroinflammation, accompanied by significant motor impairments. These effects were observed both in transgenic mice co-expressing PME-1 and human \u03b1-Syn at 9 months of age, and in PME-1 overexpressing mice six months after intrastriatal injection of \u03b1-Syn PFF. In contrast, LCMT-1 overexpression reduced \u03b1-Syn phosphorylation and aggregation, and provided robust neuroprotection, leading to improved motor outcomes in both synucleinopathy models. These findings underscore the critical role of PP2A methylation dynamics in regulating \u03b1-Syn toxicity. Accordingly, targeting the PP2A methylation machinery represents a promising therapeutic strategy to mitigate \u03b1-Syn-induced neurodegeneration and slow the progression of synucleinopathies.<\/jats:p>","DOI":"10.1038\/s41420-026-03045-7","type":"journal-article","created":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T17:02:34Z","timestamp":1774371754000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Protein phosphatase 2A methylation state impacts \u03b1-synucleinopathy in mouse models"],"prefix":"10.1038","volume":"12","author":[{"given":"Santhosh","family":"Maddila","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kambiz","family":"Hassanzadeh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5399-3478","authenticated-orcid":false,"given":"Faheem","family":"Ullah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Russell E.","family":"Nichols","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9937-412X","authenticated-orcid":false,"given":"M. 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