Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA.
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
Cell Mol Life Sci. 2020 Mar;77(6):977-996. doi: 10.1007/s00018-019-03302-2. Epub 2019 Sep 24.
The polyglutamine (polyQ) diseases are a group of nine fatal, adult-onset neurodegenerative disorders characterized by the misfolding and aggregation of mutant proteins containing toxic expansions of CAG/polyQ tracts. The heat shock protein 90 and 70 (Hsp90/Hsp70) chaperone machinery is a key component of cellular protein quality control, playing a role in the regulation of folding, aggregation, and degradation of polyQ proteins. The ability of Hsp70 to facilitate disaggregation and degradation of misfolded proteins makes it an attractive therapeutic target in polyQ diseases. Genetic studies have demonstrated that manipulation of Hsp70 and related co-chaperones can enhance the disaggregation and/or degradation of misfolded proteins in models of polyQ disease. Therefore, the development of small molecules that enhance Hsp70 activity is of great interest. However, it is still unclear if currently available Hsp70 modulators can selectively enhance disaggregation or degradation of misfolded proteins without perturbing other Hsp70 functions essential for cellular homeostasis. This review discusses the multifaceted role of Hsp70 in protein quality control and the opportunities and challenges Hsp70 poses as a potential therapeutic target in polyQ disease.
多聚谷氨酰胺（polyQ）疾病是一组由含有毒性 CAG/polyQ 重复序列的突变蛋白错误折叠和聚集引起的九个致命的成年发病的神经退行性疾病。热休克蛋白 90 和 70（Hsp90/Hsp70）伴侣蛋白机器是细胞蛋白质量控制的关键组成部分，在调节 polyQ 蛋白的折叠、聚集和降解中发挥作用。Hsp70 促进错误折叠蛋白解聚和降解的能力使其成为 polyQ 疾病的一个有吸引力的治疗靶点。遗传研究表明，Hsp70 和相关共伴侣的操纵可以增强 polyQ 疾病模型中错误折叠蛋白的解聚和/或降解。因此，开发增强 Hsp70 活性的小分子具有重要意义。然而，目前尚不清楚现有的 Hsp70 调节剂是否可以选择性地增强错误折叠蛋白的解聚或降解，而不干扰其他对细胞内稳态至关重要的 Hsp70 功能。本文综述了 Hsp70 在蛋白质质量控制中的多方面作用，以及 Hsp70 作为 polyQ 疾病潜在治疗靶点所带来的机遇和挑战。
