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

• 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
• 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' 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

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.

项目摘要 阿尔茨海默病的特征在于由淀粉样蛋白-β（Ab）形成的斑块和由淀粉样蛋白-β（Ab）形成的缠结。 磷酸化的tau蛋白，而帕金森病和路易体痴呆的特征是聚集 磷酸化的α-突触核蛋白（a-Syn）。然而，这些蛋白质的聚集体以高频率共同出现在 患有神经退行性疾病的个体的大脑，这种共同发生与更快速的 神经变性这种重叠，以及来自细胞和动物模型的证据表明， a-Syn、Ab和tau之间的致病性相互作用知之甚少， 这些复杂的衰弱性疾病的治疗上易处理的靶点仍然是主要的未满足的医疗需求。 我们假设蛋白磷酸酶2A（PP 2A）在介导这些相互作用中起着核心作用， 驱动神经退行性变，而这个主调节器的去甲基化酶，PP 2A甲基酯酶， PME-1是一种可行的疾病修饰治疗靶点。PP 2A使疾病相关形式去磷酸化 a-Syn，tau和淀粉样蛋白-b前体蛋白（APP）的表达，并且其本身因反应性蛋白水平的增加而失调。 这也是患病大脑的一个特征。此外，PME-1水平增加，PP 2A水平降低。 去甲基化，因此在受这些疾病影响的大脑中活动减退。重要的是，抑制PME-1 保护小鼠免于单独暴露于致病形式的a-Syn和Ab。在这里，我们建议审查 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PP 2A受损的新型小鼠模型暴露于这些蛋白质组合的后果 PME-1表达增加导致的甲基化和活性。在目标2中，我们将测试PME-1抑制， 使用遗传和药理学方法，保护免受暴露于 这些致病蛋白的组合。这些研究的结果将阐明潜在的机制 a-Syn-、Ab-和tau-相关的共病理学，并测试PME-1抑制作为疾病调节剂的潜力。 治疗这些疾病。