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

项目总结 阿尔茨海默病的特征是由淀粉样β蛋白(Ab)形成的斑块和由 磷酸化的tau蛋白，而帕金森氏病和路易体痴呆的特点是聚集体 磷酸化的α-突触核蛋白(a-Syn)。然而，这些蛋白质聚集在一起的频率很高 患有神经退行性疾病的人的大脑，这种共同发生与更快的 神经退行性变。这种重叠，加上来自细胞和动物模型的证据，表明了协同作用 A-Syn、Ab和tau之间的致病相互作用知之甚少，并鉴定了新的 对于这些复杂的衰弱疾病，在治疗上容易处理的靶点仍然是一个主要的未得到满足的医疗需求。 我们假设蛋白磷酸酶2A(PP2A)在调节这些相互作用中起着核心作用，并且 驱动神经退行性变，这个主要调节因子的去甲基酶，PP2A甲基酯酶， PME-1是一种可行的疾病修饰治疗靶点。PP2A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，并且自身受反应性水平增加的影响而失调 氧气也是患病大脑的一个特征。此外，PME-1水平增加，PP2A 去甲基化，因此，在受这些疾病影响的大脑中，活动不足。重要的是，抑制PME-1 保护小鼠免受致病形式的α-Syn和抗体的影响。在这里，我们建议研究一下 PME-1在致病蛋白协同作用中的作用及其治疗作用 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。 在PP2A受损的新小鼠模型中暴露于这些蛋白质组合的后果 甲基化和活性是由于PME-1表达增加所致。在目标2中，我们将测试PME-1抑制， 使用遗传和药理学方法，防止暴露于 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相关的共同病理，并测试PME-1抑制作为疾病改良剂的可能性 这些疾病的治疗方法。

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.