神经变性构象病与热休克蛋白 - 药学学报.DOCVIP

神经变性构象病与热休克蛋白 孔祥臣*, 鲍秀琦, 刘耕陶 (中国医学科学院、北京协和医学院药物研究所, 北京 ) 摘要: 许多神经退行性疾病的发生是由蛋白质错误折叠和聚集引起的, 这类疾病统称为神经变性构象病。基因突变、环境因素以及蛋白质质控系统 (泛素-蛋白酶体系统和自吞噬-溶酶体系统) 功能的失常, 都能导致蛋白质错误折叠并聚集而引发疾病。本文综述了引起蛋白质错误折叠和聚集的相关因素和机制、蛋白质错误折叠在神经退行性疾病发病中的作用以及诱导热休克蛋白作为一种新途径治疗神经变性构象病的研究进展。 蛋白质错误折叠; 神经变性构象病; β-淀粉样蛋白; α-突触核蛋白; 热休克蛋白A 文章编号: 0513-4870 (2010) 11-1333-06 Neurodegenerative conformational disease and heat shock proteins KONG Xiang-chen*, BAO Xiu-qi, LIU Geng-tao (Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China) Abstract: Many major neurodegenerative diseases are associated with proteins misfolding and aggregation, which are also called “neurodegenerative conformational disease”. The interaction of gene mutation and environmental factors are probably primary events resulting in oligomer and aggregate formations of proteins. Moreover, the dysfunctions of protein control systems, i.e. the ubiquitin-proteasome system and autophagy- lysosomal system, also contribute to the neurodegenerative process. The present review mainly summarizes protein misfolding and aggregation in the development of neurodegenerative conformational disease and the underling mechanisms, as well as upregulation of heat shock proteins as a promising treatment method for this kind of disease. Key words: protein misfolding; neurodegenerative conformational disease; β-amyloid; α-synuclein; heat shock protein (蛋白质是维持生命必不可少的物质, 是构成所有有机体的物质基础和细胞功能的执行者。人类至 少有3万种不同的蛋白质, 每种蛋白都有其特定的氨基酸序列和空间构象以履行它们特定的功能。蛋白 质特定的空间构象是其发挥各种生物功能的结构基础。很多情况下蛋白质的氨基酸序列没有改变, 但蛋白质的空间构象由于某些因素发生了改变导致蛋白质错误折叠并聚集, 失去了原有的生物学功能, 从而引发疾病。迄今已发现20多种由蛋白质的错误折叠和聚集引发的疾病。许多神经退行性疾病发生与 蛋白质的错误折叠和聚集有关, 包括阿尔茨海默病 (Alzheimer’s disease, AD)、帕金森病 (Parkinson’s disease, PD)、朊蛋白病 (prion disease)、多聚谷酰胺疾病 (polyglutamine disease)、家族性肌萎缩侧索硬化症 (familial amyotrophic lateral sclerosis, ALS) 等多种疾病, 这