Proteasome function in Alzheimer's Disease

蛋白酶体在阿尔茨海默病中的功能

基本信息

  • 批准号:
    10611994
  • 负责人:
  • 金额:
    $ 46.08万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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)的特征在于错误折叠和受损的细胞内蛋白质的积累。 proteins.早期积累并在疾病发病机制中发挥重要作用的主要物种是 淀粉样蛋白β(Aβ)、Tau,有时还有α-突触核蛋白(α-syn)。大量的文献支持这样一种观点, 细胞的蛋白质降解系统在AD中没有足够的功能来清除这些错误折叠的蛋白质。 细胞降解这种错误折叠或受损蛋白质的主要系统是泛素 蛋白酶体系统(UPS)。我们最近发现,病理相关的Aβ,Tau, 和α-syn可以有效和直接抑制分离的20 S和26 S蛋白酶体,甚至抑制泛素- 体外依赖性蛋白质降解。根据我们的初步数据,我们假设这种病理性的 寡聚体通过直接抑制神经元中的蛋白酶体功能而促成AD发病机制。我们做什么 尚不清楚这种寡聚体对蛋白酶体的抑制是否会引起AD相关的神经元功能障碍, 我们也不知道其中的分子机制我们建议通过以下方式填补这一知识空白:1) 阐明这些寡聚体在体外和体内抑制蛋白酶体的精确机制2) 产生超活性或对抑制性寡聚体有抗性的蛋白酶体,和3)测试是否超活性 或寡聚体抗性蛋白酶体可以挽救AD的细胞和动物模型中的神经元功能。我们 该提议是创新的,因为我们已经产生了非常新颖的动物模型和初步数据, 支持一种新的机制假说,它解决了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 AD相关寡聚体引起的蛋白酶体损伤可引起神经元功能障碍。这种贡献 重要的是,它将填补我们知识的空白,证明病理性寡聚体 与AD相关的蛋白酶抑制剂通过直接抑制蛋白酶体至少部分地引起神经元功能障碍。在 此外,本研究还将证明蛋白酶体激活是否可以保护神经元免受AD相关的损伤。 蛋白毒性预计这些结果将产生积极影响,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, 这是一种可以用于药理学开发的机制。

项目成果

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David Matthew Smith其他文献

David Matthew Smith的其他文献

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{{ truncateString('David Matthew Smith', 18)}}的其他基金

Proteasome function in Alzheimer's Disease
蛋白酶体在阿尔茨海默病中的功能
  • 批准号:
    10160738
  • 财政年份:
    2020
  • 资助金额:
    $ 46.08万
  • 项目类别:
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
  • 财政年份:
    2020
  • 资助金额:
    $ 46.08万
  • 项目类别:
Proteasome function in Alzheimer's Disease
蛋白酶体在阿尔茨海默病中的功能
  • 批准号:
    9973659
  • 财政年份:
    2020
  • 资助金额:
    $ 46.08万
  • 项目类别:
Mechanisms regulating proteasomal substrate degradation
蛋白酶体底物降解的调节机制
  • 批准号:
    8694173
  • 财政年份:
    2014
  • 资助金额:
    $ 46.08万
  • 项目类别:
Mechanisms regulating proteasomal substrate degradation
蛋白酶体底物降解的调节机制
  • 批准号:
    10247747
  • 财政年份:
    2014
  • 资助金额:
    $ 46.08万
  • 项目类别:
Mechanisms regulating proteasomal substrate degradation
蛋白酶体底物降解的调节机制
  • 批准号:
    9301593
  • 财政年份:
    2014
  • 资助金额:
    $ 46.08万
  • 项目类别:
Mechanisms regulating proteasomal substrate degradation
蛋白酶体底物降解的调节机制
  • 批准号:
    8875711
  • 财政年份:
    2014
  • 资助金额:
    $ 46.08万
  • 项目类别:
Mechanisms regulating proteasomal substrate degradation
蛋白酶体底物降解的调节机制
  • 批准号:
    10474492
  • 财政年份:
    2014
  • 资助金额:
    $ 46.08万
  • 项目类别:
Mechanisms regulating proteasomal substrate degradation
蛋白酶体底物降解的调节机制
  • 批准号:
    10022500
  • 财政年份:
    2014
  • 资助金额:
    $ 46.08万
  • 项目类别:

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