The role and therapeutic potential of Hsp90, Hsp70, and smaller heat shock proteins in peripheral and central neuropathies.
The role and therapeutic potential of Hsp90, Hsp70, and smaller heat shock proteins in peripheral and central neuropathies.
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DOI：
10.1002/med.21729
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发表时间：
2021-01
影响因子：
13.3
通讯作者：
Blagg BSJ
中科院分区：
文献类型：
--
作者：
Chaudhury S;Keegan BM;Blagg BSJ
热休克蛋白（Hsps）是一种分子伴侣，在热休克反应（HSR）的激活中也起着重要作用。HSR是一种进化保守和保护机制，用于对抗异常的生理条件、应激源和疾病状态，例如癌症和/或神经变性中的那些。在正常细胞中，调节HSR的转录因子热休克因子-1（HSF-1）保持在休眠的多蛋白复合物中，该复合物在与分子伴侣（Hsp 90、Hsp 70等）缔合后形成，辅伴侣蛋白和客户蛋白。然而，在细胞应激下，HSF-1从Hsp 90解离并诱导Hsp 70的转录上调以提供对所遇到的细胞应激的保护。作为外周和中枢神经病变的结果，细胞应激发生并导致未折叠和/或错误折叠蛋白质的积累，这可以通过HSR的激活来平衡。由于Hsp 90是HSR的主要调节因子，因此通过小分子调节Hsp 90代表了针对外周和中枢神经病的有吸引力的治疗方法。
Heat shock proteins (Hsps) are molecular chaperones that also play important roles in activation of the heat shock response (HSR). The HSR is an evolutionary conserved and protective mechanism that is used to counter abnormal physiological conditions, stressors, and disease states, such as those exemplified in cancer and/or neurodegeneration. In normal cells, heat shock factor-1 (HSF-1), the transcription factor that regulates the HSR, remains in a dormant multi-protein complex that is formed upon association with chaperones (Hsp90, Hsp70 etc.), co-chaperones, and client proteins. However, under cellular stress, HSF-1 dissociates from Hsp90 and induces the transcriptional upregulation of Hsp70 to afford protection against the encountered cellular stress. As a consequence of both peripheral and central neuropathies, cellular stress occurs and results in the accumulation of unfolded and/or misfolded proteins, which can be counterbalanced by activation of the HSR. Since Hsp90 is the primary regulator of the HSR, modulation of Hsp90 by small molecules represents an attractive therapeutic approach against both peripheral and central neuropathies.
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