Protein accumulation and aggregation with a concomitant loss of proteostasis often contribute to neurodegenerative diseases, and the ubiquitin-proteasome system plays a major role in protein degradation and proteostasis. Here, we show that three different proteins from Alzheimer's, Parkinson's, and Huntington's disease that misfold and oligomerize into a shared three-dimensional structure potently impair the proteasome. This study indicates that the shared conformation allows these oligomers to bind and inhibit the proteasome with low nanomolar affinity, impairing ubiquitin-dependent and ubiquitin-independent proteasome function in brain lysates. Detailed mechanistic analysis demonstrates that these oligomers inhibit the 20S proteasome through allosteric impairment of the substrate gate in the 20S core particle, preventing the 19S regulatory particle from injecting substrates into the degradation chamber. These results provide a novel molecular model for oligomer-driven impairment of proteasome function that is relevant to a variety of neurodegenerative diseases, irrespective of the specific misfolded protein that is involved.

中文翻译：

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与神经退行性疾病相关的寡聚体引起的蛋白酶体损伤的常见机制。

蛋白质的积累和聚集以及随之而来的蛋白质变形的丧失通常会导致神经退行性疾病，而泛素-蛋白酶体系统在蛋白质降解和蛋白质变形中起主要作用。在这里，我们显示了来自阿尔茨海默氏症，帕金森氏症和亨廷顿氏病的三种不同蛋白质，它们错误折叠并寡聚为一个共享的三维结构，有力地损害了蛋白酶体。这项研究表明，共有的构象允许这些寡聚物以低纳摩尔亲和力结合并抑制蛋白酶体，从而削弱脑裂解物中泛素依赖性和泛素依赖性蛋白酶体的功能。详细的机理分析表明，这些低聚物通过20S核心颗粒中底物门的变构损伤而抑制20S蛋白酶体，防止19S调节粒子将底物注入降解室。这些结果为寡聚体驱动的蛋白酶体功能受损提供了一种新颖的分子模型，该模型与多种神经退行性疾病有关，而与涉及的特定错误折叠蛋白无关。