Proteasome function in Alzheimer's Disease

蛋白酶体在阿尔茨海默病中的功能

• 批准号: 10388372
• 负责人: David Matthew Smith
• 金额: $ 46.08万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10388372
• 关键词: 26S proteasome; Address; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-42; Amyloid beta-Protein; Animal Disease Models; Animal Model; Binding; Binding Sites; Biochemical; Biological; Brain; Caenorhabditis elegans; Cell Culture Techniques; Cell model; Cell physiology; Cells; Data; Development; Disease; Disease Progression; Disease Resistance; Engineering; Face; Foundations; Genetic; Goals; Human Cell Line; Hyperactivity; Impairment; In Vitro; Individual; Knowledge; Laboratories; Life; Link; Literature; Mission; Modeling; Molecular; Molecular Conformation; Mus; Neuronal Dysfunction; Neurons; Nucleosome Core Particle; Outcome; Pathogenesis; Pathogenicity; Pathologic; Pharmacology; Play; Process; Proteasome Inhibition; Proteins; Public Health; Research; Resistance; Role; Site; Synaptic Transmission; Synaptic plasticity; System; Testing; Ubiquitin; United States National Institutes of Health; abeta oligomer; age related; alpha synuclein; base; biophysical techniques; experience; in vivo; innovation; misfolded protein; multicatalytic endopeptidase complex; mutant; neurotoxic; neurotoxicity; novel; protein degradation; proteotoxicity; small molecule; tau Proteins; therapeutic target; tool

At the cellular level Alzheimer’s disease (AD) is characterized by the accumulation of misfolded and damaged proteins. Prominent species that accumulate early and play fundamental roles in disease pathogenesis are Amyloid β (Aβ), Tau, and sometimes α-synuclein (α-syn). A vast body of literature supports the notion that the cell’s protein degradation systems do not function sufficiently enough in AD to clear these misfolded proteins. The cell’s primary system for the degradation of such misfolded or damaged proteins is the Ubiquitin Proteasome System (UPS). We have recently found that pathologically relevant oligomeric forms of Aβ, Tau, and α-syn can potently and directly inhibit isolated 20S and 26S proteasomes, even inhibiting ubiquitin- dependent protein degradation in vitro. Based on our preliminary data we hypothesize that such pathological oligomers contribute to AD pathogenesis by directly inhibiting proteasome function in neurons. What we do not know is if proteasome inhibition by such oligomers can cause AD related neuronal dysfunction, nor do we know the molecular mechanisms involved. We propose to fill this gap in knowledge by 1) elucidating the precise mechanism of proteasome inhibition by these oligomers in vitro and in vivo 2) generating proteasomes that are hyper-active or resistant to inhibitory oligomers and 3) testing if hyper-active or oligomer resistant proteasomes can rescue neuronal function in cellular and animal models of AD. Our proposal is innovative because we have generated highly novel animal model and preliminary data that supports a novel mechanistic hypotheses, which addresses a fundamental component of AD. Extending these studies will allow us to generate disease resistant proteasomes allowing us to conclusively determine if direct proteasome impairment by AD related oligomers can cause neuronal dysfunction. This contribution is significant because it will fill a gap in our knowledge by demonstrating that the pathological oligomers associated with AD cause neuronal dysfunction, at least in part, by directly inhibiting the proteasome. In addition, this study will also demonstrate if proteasome activation can protect neurons from AD related proteotoxicities. These outcomes are expected to have a positive impact because they demonstrate that the proteasome is a prime therapeutic target to treat Alzheimer’s disease and provides a precise molecular mechanism that can be exploited for pharmacological development.

在细胞水平，阿尔茨海默氏病（AD）的特征是折叠和损坏的积累 早期积累并在疾病发病机理中起着基本作用的重要物种是 淀粉样β（Aβ），tau，有时是α-核蛋白（α-Syn）。大量文学支持了这样的观念 细胞的蛋白质降解系统在AD中的功能不足以清除这些错误折叠的蛋白质。 细胞的主要系统降解这种错误折叠或受损的蛋白质是泛素 蛋白酶体系统（UPS）。我们最近发现，Aβ，tau的病理相关的寡聚形式 α-syn可以潜在，直接抑制分离的20S和26S蛋白酶体，即使抑制泛素 - 依赖性蛋白质在体外降解。根据我们的初步数据，我们假设这种病理 低聚物通过直接抑制神经元的蛋白酶体功能来促进AD发病机理。我们做什么 不知道这种低聚物的蛋白酶体抑制是否会引起与AD相关的神经元功能障碍， 我们也不知道所涉及的分子机制。我们建议通过1填补这一空白1） 阐明这些低聚物在体外和体内抑制蛋白酶体抑制的精确机制） 产生对抑制性低聚物的过度活跃或抗性的蛋白酶体，3）测试如果过度活跃 耐果实蛋白酶体可以在AD的细胞和动物模型中挽救神经元功能。我们的 提案具有创新性，因为我们已经产生了高度新颖的动物模型和初步数据 支持一种新型的机械假设，该假设涉及AD的基本组成部分。扩展这些 研究将使我们能够产生抗病蛋白酶体，使我们能够最终确定是否直接 与AD相关的低聚物受到的蛋白酶体损害会引起神经元功能障碍。这个贡献是 意义重大，因为它会通过证明病理性的低聚物来填补我们的知识的空白 与AD相关的AD至少通过直接抑制蛋白酶体而引起神经元功能障碍。在 此外，这项研究还将证明蛋白酶体激活是否可以保护神经元免受与AD相关的影响 蛋白毒性。预计这些结果将产生积极的影响，因为它们表明 蛋白酶体是治疗阿尔茨海默氏病并提供精确分子的主要治疗靶标 可以探索药物开发的机制。