Department of Molecular Biosciences, Rice Institute for Biomedical Research, Northwestern University, Evanston, IL, USA.
Adv Exp Med Biol. 2020;1243:53-68. doi: 10.1007/978-3-030-40204-4_4.
Protein homeostasis (Proteostasis) is essential for correct and efficient protein function within the living cell. Among the critical components of the Proteostasis Network (PN) are molecular chaperones that serve widely in protein biogenesis under physiological conditions, and prevent protein misfolding and aggregation enhanced by conditions of cellular stress. For Alzheimer's, Parkinson's, Huntington's diseases and ALS, multiple classes of molecular chaperones interact with the highly aggregation-prone proteins amyloid-β, tau, α-synuclein, huntingtin and SOD1 to influence the course of proteotoxicity associated with these neurodegenerative diseases. Accordingly, overexpression of molecular chaperones and induction of the heat shock response have been shown to be protective in a wide range of animal models of these diseases. In contrast, for cancer cells the upregulation of chaperones has the undesirable effect of promoting cellular survival and tumor growth by stabilizing mutant oncoproteins. In both situations, physiological levels of molecular chaperones eventually become functionally compromised by the persistence of misfolded substrates, leading to a decline in global protein homeostasis and the dysregulation of diverse cellular pathways. The phenomenon of chaperone competition may underlie the broad pathology observed in aging and neurodegenerative diseases, and restoration of physiological protein homeostasis may be a suitable therapeutic avenue for neurodegeneration as well as for cancer.
蛋白质动态平衡（蛋白质稳态）对于细胞内蛋白质正确且高效的功能发挥至关重要。在蛋白质动态平衡网络（PN）的关键组成部分中，分子伴侣在生理条件下广泛参与蛋白质生物发生，并防止蛋白质错误折叠和聚集，这些错误折叠和聚集是由细胞应激条件增强的。对于阿尔茨海默病、帕金森病、亨廷顿病和肌萎缩侧索硬化症，多种分子伴侣与高度聚集倾向的蛋白质淀粉样β、tau、α-突触核蛋白、亨廷顿蛋白和 SOD1 相互作用，影响与这些神经退行性疾病相关的毒性蛋白聚集过程。因此，在这些疾病的广泛动物模型中，已经证明过表达分子伴侣和诱导热休克反应具有保护作用。相比之下，对于癌细胞，伴侣蛋白的上调会通过稳定突变致癌蛋白来促进细胞存活和肿瘤生长，从而产生不良影响。在这两种情况下，生理水平的分子伴侣最终会因错误折叠底物的持续存在而功能受损，导致全局蛋白质动态平衡下降和多种细胞途径的失调。伴侣蛋白竞争的现象可能是衰老和神经退行性疾病中广泛观察到的病理现象的基础，恢复生理蛋白质动态平衡可能是神经退行性疾病以及癌症的一种合适的治疗途径。
