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.

在细胞水平上，阿尔茨海默病（AD）的特点是错误折叠和受损细胞的积累 早期积累并在疾病发病机制中发挥重要作用的重要物种是 β 淀粉样蛋白 (Aβ)、Tau，有时还有 α-突触核蛋白 (α-syn)。大量文献支持这一观点。 在 AD 中，细胞的蛋白质降解系统无法充分发挥作用来清除这些错误折叠的蛋白质。 细胞降解此类错误折叠或受损蛋白质的主要系统是泛素 我们最近发现 Aβ、Tau 的病理相关寡聚形式。 α-syn 可以有效地直接抑制分离的 20S 和 26S 蛋白酶体，甚至抑制泛素- 根据我们的初步数据，我们认为这种病理性的蛋白质降解。 寡聚物通过直接抑制神经元中的蛋白酶体功能来促进 AD 发病机制。 不知道此类寡聚物对蛋白酶体的抑制是否会导致 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，我们建议通过以下方式填补这一知识空白。 阐明这些寡聚物在体外和体内抑制蛋白酶体的精确机制 2) 产生过度活跃或对抑制性寡聚体具有抗性的蛋白酶体，并且 3) 测试是否过度活跃 或寡聚物抗性蛋白酶体可以挽救 AD 细胞和动物模型中的神经功能。 该提案具有创新性，因为我们生成了高度新颖的动物模型和初步数据 支持一种新颖的机制假设，该假设解决了 AD 的基本组成部分。 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 AD 相关寡聚物造成的蛋白酶体损伤可导致神经元功能障碍。 意义重大，因为它将通过证明病理性低聚物来填补我们的知识空白 与 AD 相关的神经元功能障碍至少部分是通过直接抑制蛋白酶体引起的。 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 AD 相关的影响 这些结果预计会产生积极的影响，因为它们表明 蛋白酶体是治疗阿尔茨海默病的主要治疗靶点，并提供精确的分子 可用于药理学开发的机制。