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.

项目摘要在丝氨酸129处磷酸化的α-突触核蛋白是标志性的Lewy体内病理原纤维聚集体的标志帕金森氏病（PD）和痴呆症的包含物与刘易尸体，但此后的精确原因翻译修饰及其在这些疾病的发病机理中的作用尚不清楚。这个项目的目标通过研究蛋白质磷酸酶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中发挥作用。 PP2A是构成大部分丝氨酸/苏氨酸磷酸酶活性的保守酶家族并充当细胞磷酸根网络的主调节器，控制所需的关键过程 PP2A是一种由催化C亚基组成的三聚酶脚手架和一个调节性B亚基每个都由多个基因编码和多个编码剪接同工型。 PP2A的底物特异性由其亚基组成确定，该组合受到调节通过其催化C亚基的甲基化，该甲基化受到专用甲基酯酶的控制 PME-1和专用的甲基转移酶LCMT-1。负责去磷酸化的PP2A同工型 α-突触核蛋白是甲基化依赖性的，药物抑制PME-1依赖性PP2A脱甲基化减轻α-突触核蛋白转基因小鼠的表型。研究PP2A的作用及其甲基化在 α-突触核酸，我们将使用PME-1和LCMT-1表达在体内改变PP2A活性转基因小鼠。特定的目标1将通过增加的假设来测试降低pp2a甲基化的假设 PME-1表达，通过增加α-突触核蛋白的致病性来加剧α-突触核酸。 AIM 2意志检验以下假设，即通过增加的LCMT-1表达增强PP2A甲基化可以预防通过降低α-突触核蛋白的致病性来通过α-突触核酸病变。 AIM 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。在这些研究中，我们将更深入地了解PP2A在α-突触性核核病和将其作为一种潜在的疾病来改变这些疾病的治疗靶点。