Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8502, Japan.
Curr Pharm Biotechnol. 2010 Feb;11(2):188-97. doi: 10.2174/138920110790909650.
Protein misfolding and aggregation in the brain have been implicated as a common molecular pathogenesis of various neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and the polyglutamine (polyQ) diseases. The polyQ diseases are a group of nine hereditary neurodegenerative diseases, including Huntington's disease (HD) and various types of spinocerebellar ataxia (SCA), which are caused by abnormal expansions of the polyQ stretch (> 35-40 repeats) in unrelated disease-causative proteins. The expanded polyQ stretch is thought to trigger misfolding of these proteins, leading to their aggregation and accumulation as inclusion bodies in affected neurons, eventually resulting in neurodegeneration. Misfolding and aggregation of the polyQ protein are the most ideal therapeutic targets since they are the most upstream events in the pathogenic cascade, and therefore, therapeutic approaches using molecular chaperones, which prevent protein misfolding and assist the refolding of misfolded proteins, are being extensively investigated. Indeed, a variety of molecular chaperones such as Hsp70 and Hsp40 have been demonstrated to exert therapeutic effects against various experimental models of the polyQ diseases. Furthermore, toward developing pharmacological therapies, small chemical activators of heat shock transcription factor 1 (HSF1) such as geldanamycin and its derivative 17-AAG, which induce multiple endogenous molecular chaperones, have been proven to be effective not only in polyQ disease models, but also in other neurodegenerative disease models. We hope that brain-permeable molecular chaperone inducers will be developed as drugs against a wide range of neurodegenerative diseases in the near future.
蛋白质在脑内错误折叠和聚集被认为是各种神经退行性疾病的共同分子发病机制，包括阿尔茨海默病、帕金森病、肌萎缩侧索硬化症和多聚谷氨酰胺（polyQ）疾病。polyQ 疾病是一组由九个遗传性神经退行性疾病组成的疾病，包括亨廷顿病（HD）和各种类型的脊髓小脑共济失调（SCA），这些疾病是由相关疾病致病蛋白中 polyQ 延伸（>35-40 个重复）的异常扩展引起的。扩展的 polyQ 延伸被认为会触发这些蛋白质的错误折叠，导致它们聚集并在受影响的神经元中积累为包涵体，最终导致神经退行性变。polyQ 蛋白的错误折叠和聚集是最理想的治疗靶点，因为它们是致病级联反应中最上游的事件，因此，使用分子伴侣的治疗方法，这些分子伴侣可以防止蛋白质错误折叠并协助错误折叠的蛋白质重折叠，正在被广泛研究。事实上，已经证明多种分子伴侣，如 Hsp70 和 Hsp40，对各种 polyQ 疾病模型具有治疗作用。此外，为了开发药理学治疗方法，小分子热休克转录因子 1（HSF1）激活剂，如 geldanamycin 和其衍生物 17-AAG，可诱导多种内源性分子伴侣，已被证明不仅在 polyQ 疾病模型中有效，而且在其他神经退行性疾病模型中也有效。我们希望在不久的将来，能够开发出可穿透大脑的分子伴侣诱导剂，作为治疗各种神经退行性疾病的药物。
