Protein phosphatase 2A methylation state impacts α-synucleinopathy in mouse models.

The accumulation of aggregated alpha-Synuclein (α-Syn) in Lewy bodies and Lewy neurites is a hallmark of Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB), and phosphorylation of α-Syn at Ser129 is a key pathological marker in synucleinopathies. The heterotrimeric enzyme protein phosphatase 2A (PP2A), and specifically its B55α containing isoform, which dephosphorylates phospho-S129-α-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 α-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 α-Syn preformed fibrils (PFF) injections. A battery of behavioral tests was conducted to assess motor and cognitive function, followed by brain analyses quantifying phosphorylated α-Syn aggregates, neuronal toxicity, and neuroinflammatory responses, thereby evaluating how modulation of this axis influences α-Syn pathology. Overexpression of PME-1 in forebrain neurons exacerbated α-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 α-Syn at 9 months of age, and in PME-1 overexpressing mice six months after intrastriatal injection of α-Syn PFF. In contrast, LCMT-1 overexpression reduced α-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 α-Syn toxicity. Accordingly, targeting the PP2A methylation machinery represents a promising therapeutic strategy to mitigate α-Syn-induced neurodegeneration and slow the progression of synucleinopathies.