PME-1: Pathogenetic Role and Therapeutic Opportunity in Neurodegenerative Mixed Proteinopathies

PME-1：神经退行性混合蛋白病的致病作用和治疗机会

基本信息

批准号：
10595891
负责人：
M. Maral Mouradian
金额：
$ 165.31万
依托单位：
RUTGERS BIOMEDICAL AND HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-01 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10595891
关键词：
Acceleration Affect Alzheimer&apos s Disease Amyloid beta-Protein Amyloid beta-Protein Precursor Animal Model Automobile Driving Autopsy Behavioral Biochemical Biological Availability Brain Brain Diseases Brain Injuries Calcium Catalytic Domain Cell model Chemicals Complex Corpus striatum structure Data Dementia with Lewy Bodies Disease Disease Progression Enzymes Exposure to Frequencies Functional disorder Genetic Heterozygote Hippocampus Holoenzymes Impairment Individual Injections Knock-in Knock-out Mediating Medical Methylation Modification Mus Nerve Degeneration Nervous System Physiology Neurodegenerative Disorders Neurofibrillary Tangles Oral Oral cavity Oxidative Stress Parkinson Disease Pathogenicity Pathologic Pathology Persons Phenotype Phosphorylation Play Prevention Process Production Protein Dephosphorylation Protein Inhibition Protein Isoforms Protein Overexpression Protein phosphatase Proteins Reactive Oxygen Species Role Severities Testing Therapeutic Therapeutic Effect Transgenic Mice Transgenic Organisms alpha synuclein behavior test behavioral phenotyping demethylation experimental study inhibitor mitochondrial dysfunction mouse model neuropathology novel novel therapeutics overexpression pharmacologic phosphoneuroprotein 14 pre-formed fibril prevent protein aggregation protein methylesterase synucleinopathy tau Proteins tau interaction tau-1 therapeutic target

项目摘要

PROJECT SUMMARY Alzheimer’s disease is characterized by plaques formed by amyloid-beta (Ab) and tangles formed by phosphorylated tau, while Parkinson’s disease and dementia with Lewy bodies are characterized by aggregates of phosphorylated a-synuclein (a-Syn). However, aggregates of these proteins co-occur with high frequency in the brains of individuals with neurodegenerative disorders, and this co-occurrence is coincident with more rapid neurodegeneration. This overlap, together with evidence from cell and animal models point to synergistic pathogenic interactions among a-Syn, Ab, and tau that are poorly understood, and identifying novel therapeutically tractable targets for these complex debilitating disorders remains a major unmet medical need. We hypothesize that protein phosphatase 2A (PP2A) plays a central role in mediating these interactions and driving neurodegeneration, and that the demethylating enzyme of this master regulator, PP2A methylesterase, PME-1, is a viable therapeutic target for disease modification. PP2A dephosphorylates disease-associated forms of a-Syn, tau, and amyloid-b precursor protein (APP), and is itself dysregulated by increased levels of reactive oxygen species that are also a feature of diseased brains. In addition, PME-1 levels are increased and PP2A is demethylated and, therefore, hypoactive in brains affected with these diseases. Importantly, inhibiting PME-1 protects mice against individual exposure to pathogenic forms of a-Syn and Ab. Here, we propose to examine the role of PME-1 in the synergistic interactions among these pathogenic proteins as well as the therapeutic potential of inhibiting PME-1. In Aim 1, we will test the behavioral, biochemical, and neuropathological consequences of exposure to combinations of these proteins using novel mouse models with impaired PP2A methylation and activity due to increased PME-1 expression. And in Aim 2, we will test whether PME-1 inhibition, using genetic and pharmacological approaches, protects against the phenotype resulting from exposure to combinations of these pathogenic proteins. The results of these studies will elucidate the mechanisms underlying a-Syn-, Ab-, and tau-related co-pathologies, and test the potential of PME-1 inhibition as a disease modifying therapeutic approach for these disorders.

项目概要阿尔茨海默氏病的特点是由淀粉样蛋白 (Ab) 形成的斑块和由淀粉样蛋白 (Ab) 形成的缠结磷酸化 tau 蛋白，而帕金森病和路易体痴呆症的特点是聚集然而，这些蛋白质的聚集体以高频率同时出现。患有神经退行性疾病的个体的大脑，这种同时发生与更快速的发生一致这种重叠以及来自细胞和动物模型的证据表明存在协同作用。 a-Syn、Ab 和 tau 之间的致病相互作用知之甚少，并确定新的这些复杂的衰弱性疾病的治疗目标仍然是一个未满足的主要医疗需求。我们发现蛋白磷酸酶 2A (PP2A) 在介导这些相互作用中发挥着核心作用，并且驱动神经退行性变，并且这个主调节器的去甲基化酶 PP2A 甲酯酶， PME-1 是疾病修饰的可行治疗靶点。 a-Syn、tau 和淀粉样蛋白-b 前体蛋白 (APP) 的活性，并且其本身因反应性水平增加而失调氧也是患病大脑的一个特征。此外，PME-1 水平升高，PP2A 水平升高。去甲基化，因此在受这些疾病影响的大脑中活性低下，重要的是抑制 PME-1。保护小鼠免受个体暴露于致病形式的 a-Syn 和 Ab 的影响。在这里，我们建议进行检查。 PME-1 在这些致病蛋白之间的协同相互作用中的作用以及治疗作用抑制 PME-1 的潜力在目标 1 中，我们将测试行为、生化和神经病理学。使用 PP2A 受损的新型小鼠模型暴露于这些蛋白质组合的后果由于 PME-1 表达增加而导致的甲基化和活性在目标 2 中，我们将测试 PME-1 是否受到抑制，使用遗传和药理学方法，防止因暴露于环境而产生的表型这些致病蛋白的组合将阐明其潜在机制。 a-Syn-、Ab- 和 tau 相关的共同病理学，并测试 PME-1 抑制作为疾病修饰的潜力这些疾病的治疗方法。