Leucine Carboxyl Methyltransferase Downregulation And Protein Phosphatase Methylesterase Upregulation Contribute Toward The Inhibition Of Protein Phosphatase 2a By Alpha-Synuclein

The pathology of Parkinson's disease (PD) is characterized by intracellular neurofibrillary tangles of phosphorylated alpha-synuclein (alpha-syn). Protein phosphatase 2A (PP2A) is responsible for alpha-syn dephosphorylation. Previous work has demonstrated that alpha-syn can regulate PP2A activity. However, the mechanisms underlying alpha-syn regulation of PP2A activity are not well understood. In this study, we found that alpha-syn overexpression induced increased alpha-syn phosphorylation at serine 129 (Ser129), and PP2A inhibition, in vitro and in vivo. alpha-syn overexpression resulted in PP2A demethylation. This demethylation was mediated via downregulated leucine carboxyl methyltransferase (LCMT-1) expression, and upregulated protein phosphatase methylesterase (PME1) expression. Furthermore, LCMT-1 overexpression, or PME-1 inhibition, reversed alpha-syn-induced increases in alpha-syn phosphorylation and apoptosis. In addition to posttranslational modifications of the catalytic subunit, regulatory subunits are involved in the regulation of PP2A activity. We found that the levels of regulatory subunits which belong to the PPP2R2 subfamily, not the PPP2R5 subfamily, were downregulated in the examined brain regions of transgenic mice. Our work identifies a novel mechanism to explain how alpha-syn regulates PP2A activity, and provides the optimization of PP2A methylation as a new target for PD treatment.