Proteasome function in Alzheimer's Disease

在细胞水平上，阿尔茨海默病(AD)的特征是错误折叠和损伤的堆积 蛋白质。早期积累并在疾病发病机制中发挥基础作用的突出物种有 淀粉样蛋白β(Aβ)，Tau，有时还有α-突触核蛋白(α-SYN)。大量文献支持这样一种观点，即 在阿尔茨海默病中，细胞的蛋白质降解系统功能不足以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，病理上相关的Aβ，Tau， α-SYN能有效地直接抑制分离的20S和26S蛋白酶体，甚至抑制泛素-2。 依赖于蛋白质的体外降解。根据我们的初步数据，我们假设这种病态的 寡聚体通过直接抑制神经元中的蛋白酶体功能参与AD的发病。我们要做的是 目前尚不清楚这种寡聚体对蛋白酶体的抑制是否会导致AD相关的神经元功能障碍， 我们也不知道其中涉及的分子机制。我们建议通过以下方式填补这一知识空白1) 阐明这些寡聚体在体内外抑制蛋白酶体的确切机制2 产生高活性或对抑制性低聚体具有抵抗力的蛋白酶体，以及3)测试是否高活性 或者，寡聚体抗性蛋白酶体可以挽救AD细胞和动物模型的神经元功能。我们的 这项提议是创新的，因为我们产生了非常新颖的动物模型和初步数据， 支持一种新的机械论假说，它解决了AD的一个基本组成部分。扩展这些功能 研究将使我们能够产生抗病蛋白酶体，从而使我们最终确定是否直接 AD相关寡聚体的蛋白酶体损伤可导致神经元功能障碍。这一贡献是 意义重大，因为它将通过证明病理性低聚物填补我们知识的空白 与AD相关导致神经元功能障碍，至少部分是通过直接抑制蛋白酶体来实现的。在……里面 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相关疾病的影响 蛋白质毒性。这些结果预计将产生积极影响，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，并提供了一种精确的分子 可用于药理开发的机制。

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.