Heat shock proteins in neurodegenerative diseases: Pathogenic roles and therapeutic implications
Heat shock proteins in neurodegenerative diseases: Pathogenic roles and therapeutic implications
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DOI：
10.3109/02656730903315823
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发表时间：
2009-01-01
影响因子：
3.1
通讯作者：
Sobue, Gen
中科院分区：
文献类型：
--
作者：
Adachi, Hiroaki;Katsuno, Masahisa;Sobue, Gen
包括肌萎缩性侧索硬化症、帕金森病、阿尔茨海默病和多聚谷氨酰胺（polyQ）疾病在内的神经退行性疾病被认为是由蛋白质错误折叠引起的。热休克蛋白（Heat shock proteins，HSPs）主要作为分子伴侣，在蛋白质的折叠和质量控制中发挥重要作用。神经退行性疾病的组织病理学标志是在神经系统的靶区域中的残留神经元中的致病蛋白的积累和/或包含。包涵体联合收割机与分子伴侣途径和泛素-蛋白酶体的许多组分结合，提高了突变蛋白的错误折叠和改变的降解可能参与神经退行性疾病的发病机制的可能性。在神经元细胞和小鼠模型中，HSPs的过表达已被报道可以减少包涵体的数量和大小以及致病蛋白的积累，并改善表型。Hsp90抑制剂也通过选择性蛋白酶体降解其客户蛋白发挥治疗作用。使用动物模型阐明其病理生理学已经导致疾病修饰药物的开发，即，热休克蛋白90抑制剂和热休克蛋白诱导剂，抑制神经元变性的病理过程。这些发现可能为开发神经退行性疾病的HSP相关疗法提供基础。
Neurodegenerative diseases including amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, and polyglutamine (polyQ) diseases are thought to be caused by protein misfolding. Heat shock proteins (HSPs), which function mainly as molecular chaperones, play an important role in the folding and quality control of proteins. The histopathological hallmark of neurodegenerative diseases is accumulation and/or inclusions of the disease-causing proteins in residual neurons in targeted regions of the nervous system. The inclusions combine with many components of molecular chaperone pathways and ubiquitin-proteasome, raising the possibility that misfolding and altered degradation of mutant proteins may be involved in the pathogenesis of neurodegenerative diseases. Overexpression of HSPs has been reported to reduce the number and size of inclusions and accumulation of disease-causing proteins, and ameliorate the phenotypes in neuronal cell and mouse models. Hsp90 inhibitors also exert therapeutic effects through selective proteasome degradation of its client proteins. Elucidation of its pathophysiology using animal models has led to the development of disease-modifying drugs, i.e., Hsp90 inhibitor and HSP inducer, which inhibit the pathogenic process of neuronal degeneration. These findings may provide the basis for development of an HSP-related therapy for neurodegenerative diseases.