Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, School of Basic Medicine, Medical College, Qingdao University, Qingdao, China.
Cell Death Dis. 2021 Feb 4;12(2):154. doi: 10.1038/s41419-021-03441-0.
Proteasome is the principal hydrolytic machinery responsible for the great majority of protein degradation. The past three decades have testified prominent advances about proteasome involved in almost every aspect of biological processes. Nonetheless, inappropriate increase or decrease in proteasome function is regarded as a causative factor in several diseases. Proteasome abundance and proper assembly need to be precisely controlled. Indeed, various neurodegenerative diseases including Parkinson's disease (PD) share a common pathological feature, intracellular protein accumulation such as α-synuclein. Proteasome activation may effectively remove aggregates and prevent the neurodegeneration in PD, which provides a potential application for disease-modifying treatment. In this review, we build on the valuable discoveries related to different types of proteolysis by distinct forms of proteasome, and how its regulatory and catalytic particles promote protein elimination. Additionally, we summarize the emerging ideas on the proteasome homeostasis regulation by targeting transcriptional, translational, and post-translational levels. Given the imbalanced proteostasis in PD, the strategies for intensifying proteasomal degradation are advocated as a promising approach for PD clinical intervention.
蛋白酶体是负责绝大多数蛋白质降解的主要水解机制。在过去的三十年中，蛋白酶体在几乎所有生物过程方面的参与都取得了显著的进展。然而，蛋白酶体功能的不适当增加或减少被认为是几种疾病的一个致病因素。蛋白酶体的丰度和适当的组装需要被精确地控制。事实上，包括帕金森病 (PD) 在内的各种神经退行性疾病具有一个共同的病理特征，即细胞内蛋白质的积累，如α-突触核蛋白。蛋白酶体的激活可以有效地清除聚集体并防止 PD 中的神经退行性变，这为疾病修饰治疗提供了一个潜在的应用。在这篇综述中，我们基于不同形式的蛋白酶体对不同类型的蛋白水解的有价值的发现，以及其调节和催化颗粒如何促进蛋白质的清除。此外，我们总结了靶向转录、翻译和翻译后水平的蛋白酶体动态平衡调节的新观点。鉴于 PD 中失衡的蛋白质稳态，增强蛋白酶体降解的策略被认为是 PD 临床干预的一种有前途的方法。
