蛋白酶体激活以对抗蛋白毒性。

Loss of proteome fidelity leads to the accumulation of non-native protein aggregates and oxidatively damaged species: hallmarks of an aged cell. These misfolded and aggregated species are often found, and suggested to be the culpable party, in numerous neurodegenerative diseases including Huntington's, Parkinson's, Amyotrophic Lateral Sclerosis (ALS), and Alzheimer's Diseases (AD). Many strategies for therapeutic intervention in proteotoxic pathologies have been put forth; one of the most promising is bolstering the efficacy of the proteasome to restore normal proteostasis. This strategy is ideal as monomeric precursors and oxidatively damaged proteins, so called "intrinsically disordered proteins" (IDPs), are targeted by the proteasome. This review will provide an overview of disorders in proteins, both intrinsic and acquired, with a focus on susceptibility to proteasomal degradation. We will then examine the proteasome with emphasis on newly published structural data and summarize current known small molecule proteasome activators.

蛋白质组保真度的丧失会导致非天然蛋白质聚集体和氧化损伤物种的积累

这是衰老细胞的标志。在许多神经退行性疾病中，包括亨廷顿氏病、帕金森氏病、肌萎缩侧索硬化症（ALS）和阿尔茨海默病（AD），经常发现这些错误折叠和聚集的物质，并被认为是罪魁祸首。已经提出了许多针对蛋白质毒性病变的治疗干预策略；其中最有前途的策略之一是增强蛋白酶体的功效，以恢复正常的蛋白质稳态。这种策略非常理想，因为单体前体和氧化损伤的蛋白质，即所谓的“固有无序蛋白质”（IDPs），是蛋白酶体的靶标。本综述将概述蛋白质的内在和获得性紊乱，重点是易受蛋白酶体降解的影响。然后，我们将研究蛋白酶体，重点是新发表的结构数据，并总结当前已知的小分子蛋白酶体激活剂。