Role of PP2A methylation pathways in tau regulation

Abstract

The accumulation of filamentous lesions containing phosphorylated tau is a neuropathological hallmark of all tauopathies, including AD and frontotemporal dementia. Notably, the protein phosphatase 2A (PP2A) holoenzyme containing the PR55/Bα subunit (PP2A/Bα) specifically binds to tau and is a major tau phosphatase in vivo. PP2A catalytic C subunit is methylated on the Leu-309 residue by a dedicated leucine carboxyl methyltransferase (LCMT1), and demethylated by a specific protein phosphatase methylesterase (PME-1). This reversible process critically modulates the recruitment of specific regulatory B subunits to the (AC) core enzyme, thereby contributing to the complex regulation of PP2A biogenesis and substrate specificity. Significantly, PP2A methylation promotes the formation of PP2A/Bα. We have used cultured neuroblastoma cells and mouse models to study the link between one-carbon metabolism, LCMT1-dependent PP2A methylation and the regulation of tau phosphorylation. We have identified a novel mechanism linking LCMT1-mediated PP2A methylation pathways and tau regulation. We have shown that dietary folate deficiency and elevated levels of homocysteine can lead to significant downregulation of LCMT-1 in the mouse brain. As observed in AD autopsy brain tissue, decreased expression levels of LCMT1 in vitro and in vivo correlate with the loss of methylated PP2A and PP2A/Bα, and increased phosphorylation of tau at epitopes found in AD and non-AD tauopathies. We have preliminary evidence suggesting that the disturbance of PP2A methylation pathways could also be triggered in Parkinson's disease. Our results suggest that counteracting the loss of LCMT1 and PP2A/Bα could represent a novel therapeutic strategy to prevent or slow down tau pathology.