Abstract
The pathology of Parkinson’s disease (PD) is characterized by intracellular neurofibrillary tangles of phosphorylated α-synuclein (α-syn). Protein phosphatase 2A (PP2A) is responsible for α-syn dephosphorylation. Previous work has demonstrated that α-syn can regulate PP2A activity. However, the mechanisms underlying α-syn regulation of PP2A activity are not well understood. In this study, we found that α-syn overexpression induced increased α-syn phosphorylation at serine 129 (Ser129), and PP2A inhibition, in vitro and in vivo. α-syn overexpression resulted in PP2A demethylation. This demethylation was mediated via downregulated leucine carboxyl methyltransferase (LCMT-1) expression, and upregulated protein phosphatase methylesterase (PME-1) expression. Furthermore, LCMT-1 overexpression, or PME-1 inhibition, reversed α-syn-induced increases in α-syn phosphorylation and apoptosis. In addition to post-translational 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 α-syn regulates PP2A activity, and provides the optimization of PP2A methylation as a new target for PD treatment.
Highlights
Parkinson’s disease (PD) is a progressive neurodegenerative disorder
Our findings suggest that α-syn negatively regulates phosphatase 2A (PP2A) methylation via LCMT-1 and phosphatase methylesterase-1 (PME-1), whilst activation of LCMT-1 and inhibition of PME-1 reverses this process
Human α-syn and phosphorylated α-syn were only seen in the substantia nigra of Tg mice. They were both partly PK-resistant and PK-resistant α-syn was distributed in neuronal cytoplasm with dot-like structures (Figure 1H). These results suggest that α-syn overexpression can lead to PP2A inactivation, which contributes to increased α-syn phosphorylation and aggregation
Summary
Parkinson’s disease (PD) is a progressive neurodegenerative disorder. It is characterized by the death of dopaminergic neurons within substantia nigra, and the development of phosphorylated α-synuclein (α-syn) tangles. PP2A activity is regulated by the phosphorylation, as well as the methylation, of the PP2A catalytic subunit. PP2A methylation, which is regulated by Leucine carboxyl methyltransferase (LCMT-1) and PP2A methyltransferase (PME-1), is of great interest, due to its association with PP2A activity, as well as its role in recruiting specific substrates (Lee and Stock, 1993; Ogris et al, 1999). We investigated the mechanism underlying α-syn regulation of PP2A activity during α-syn-induced increases in α-syn phosphorylation. Our findings suggest that α-syn negatively regulates PP2A methylation via LCMT-1 and PME-1, whilst activation of LCMT-1 and inhibition of PME-1 reverses this process. These results help to elucidate the mechanisms underlying how α-syn regulates PP2A
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