# PP2A Dysregulation in the Pathogenesis of alpha-Synucleinopathies

> **NIH NIH R01** · RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL · 2021 · $411,687

## Abstract

Project Summary
α-Synuclein phosphorylated at Serine 129 is a marker of pathologic fibrillar aggregates in hallmark Lewy body
inclusions in Parkinson's disease (PD) and Dementia with Lewy Bodies, but the precise reason for this post-
translational modification and its role in the pathogenesis of these disorders remain unclear. This project aims
to address this knowledge gap by studying the role that protein phosphatase 2A (PP2A) mediated
dephosphorylation of α-synuclein plays in the molecular etiology of these disorders. PP2A is a member of a
family of conserved enzymes that constitute the majority of serine/threonine phosphatase activity in the brain
and function as master regulators of cellular phosphoregulatory networks, controlling key processes required
for protein homeostasis and cell survival. PP2A is a trimeric enzyme composed of a catalytic C subunit, a
scaffolding A subunit, and a regulatory B subunit each of which is encoded by multiple genes and multiple
splice isoforms. The substrate specificity of PP2A is determined by its subunit composition, which is regulated
by methylation of its catalytic C subunit, and this methylation is controlled by both a dedicated methylesterase,
PME-1, and a dedicated methyltransferase, LCMT-1. The PP2A isoform responsible for dephosphorylating 
α-synuclein is methylation dependent, and pharmacological inhibition of PME-1-dependent PP2A demethylation
mitigates the phenotype of α-synuclein transgenic mice. To study the role of PP2A and its methylation in 
α-synucleinopathies, we will alter PP2A activity in vivo by manipulating PME-1 and LCMT-1 expression using
genetically modified mice. Specific aim 1 will test the hypothesis that reducing PP2A methylation, via increased
PME-1 expression, exacerbates α-synucleinopathies by increasing the pathogenicity of α-synuclein. Aim 2 will
test the hypothesis that enhancing PP2A methylation, via increased LCMT-1 expression, protects against 
α-synucleinopathies by reducing the pathogenicity of α-synuclein. And aim 3 will determine if manipulating PP2A
methylation impacts α-synuclein mediated pathology through phosphorylation at Serine 129. By the completion
of these studies we will gain greater insight into the pathogenetic role of PP2A in α-synucleinopathies and
advance it as a potential disease modifying therapeutic target for these disorders.

## Key facts

- **NIH application ID:** 10133748
- **Project number:** 5R01NS101134-05
- **Recipient organization:** RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
- **Principal Investigator:** M. Maral Mouradian
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $411,687
- **Award type:** 5
- **Project period:** 2017-05-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10133748

## Citation

> US National Institutes of Health, RePORTER application 10133748, PP2A Dysregulation in the Pathogenesis of alpha-Synucleinopathies (5R01NS101134-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10133748. Licensed CC0.

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