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PP2A Dysregulation in the Pathogenesis of alpha-Synucleinopathies

α-突触核蛋白病发病机制中的 PP2A 失调

基本信息

批准号：
9920223
负责人：
M. Maral Mouradian
金额：
$ 45.15万
依托单位：
RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-05-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9920223
关键词：
Address Adult Affect Age Animal Model Animals Attenuated Autopsy Behavioral Brain Brain Diseases Catalytic Domain Cell Survival Cell model Chronic Corpus striatum structure Data Disease Enzymes Etiology Exhibits Family Feedback Genes Goals Holoenzymes Homeostasis Inclusion Bodies Individual Knowledge Lead Leucine Lewy Bodies Lewy Body Dementia Mediating Methylation Methyltransferase Modeling Modification Molecular Mus Mutant Strains Mice Nerve Degeneration Neurons Parkinson&apos s Dementia Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Pharmacology Phenotype Phosphorylation Play Post-Translational Protein Processing Prevention Process Prosencephalon Protein Dephosphorylation Protein Isoforms Protein Serine/Threonine Phosphatase Protein phosphatase Proteins Publishing RNA Splicing Reporting Role Serine Substantia nigra structure Substrate Specificity System Technology Testing Tetanus Helper Peptide Toxic effect Transgenes Transgenic Mice alpha synuclein demethylation genome editing improved in vivo inhibitor/antagonist insight member mouse synuclein alpha neuropathology novel strategies protein phosphatase methylesterase-1 proteostasis scaffold synucleinopathy therapeutic target transgene expression

项目摘要

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.

项目概要丝氨酸 129 处磷酸化的 α-突触核蛋白是标志性路易体中病理性纤维聚集体的标志物帕金森病 (PD) 和路易体痴呆症中的内含物，但这种情况的确切原因是翻译修饰及其在这些疾病发病机制中的作用仍不清楚。该项目旨在通过研究蛋白磷酸酶 2A (PP2A) 介导的作用来解决这一知识差距 α-突触核蛋白的去磷酸化在这些疾病的分子病因学中发挥着作用。 PP2A 是以下组织的成员构成大脑中丝氨酸/苏氨酸磷酸酶活性大部分的保守酶家族并作为细胞磷酸调节网络的主调节器，控制所需的关键过程用于蛋白质稳态和细胞存活。 PP2A 是一种三聚酶，由催化 C 亚基、支架A亚基和调节B亚基，每个亚基由多个基因和多个编码剪接异构体。 PP2A 的底物特异性由其亚基组成决定，亚基组成受调节通过其催化 C 亚基的甲基化，这种甲基化由专用的甲酯酶控制， PME-1 和专用甲基转移酶 LCMT-1。负责去磷酸化的 PP2A 同工型 α-突触核蛋白具有甲基化依赖性，并且对 PME-1 依赖性 PP2A 去甲基化具有药理学抑制作用减轻 α-突触核蛋白转基因小鼠的表型。研究 PP2A 及其甲基化在 α-突触核蛋白病，我们将通过使用以下方法操纵 PME-1 和 LCMT-1 表达来改变体内 PP2A 活性转基因小鼠。具体目标 1 将检验以下假设：通过增加 PME-1 表达通过增加 α-突触核蛋白的致病性而加剧 α-突触核蛋白病。目标2将检验以下假设：通过增加 LCMT-1 表达来增强 PP2A 甲基化，可以防止通过降低 α-突触核蛋白的致病性来治疗 α-突触核蛋白病。目标 3 将确定是否操纵 PP2A 甲基化通过丝氨酸 129 的磷酸化影响 α-突触核蛋白介导的病理学。通过这些研究，我们将更深入地了解 PP2A 在 α-突触核蛋白病中的致病作用，以及将其作为这些疾病的潜在疾病修饰治疗靶点。