内质网应激介导神经变性疾病错折叠蛋白的神经毒性

神经变性疾病(neurodegenerative diseases,NDD)的共同病变基础是细胞内的蛋白处理机制失效而出现错折叠蛋白的集聚并产生神经毒性[1].环境毒素作用、氧化损伤、线粒体功能失常、胞内Ca2 失衡等因素均可能与NDD的发病有关[2].但面对错折叠蛋白,细胞必然通过内质网启动未折叠蛋白反应(unfolded protein response,UPR),这就提示我们内质网应激(endoplasmic reticulum stress,ERstress)可能在NDD发病过程中起关键作用.近期研究表明,内质网应激广泛存在于各种NDD中,并介导错折叠蛋白产生神经毒性及细胞凋亡作用.这里我们主要对内质网应激在发病率最高的3种NDD中所起的作用加以阐述,以期为未来NDD的研究及治疗提供切实可行的思路.

Endoplasmic reticulum stress mediates the neurotoxic effect of misfolded proteins in neurodegenerative diseases

Endoplasmic reticulum (ER) stress can be caused by disturbances in the function of the ER with the accumulation of misfolded proteins. The ER response is characterized by unfolded protein response (UPR) causing translational attenuation, induction of ER chaperones and degradation of misfolded proteins. In case of prolonged or aggravated ER stress, cellular signals leading to apoptosis are activated. ER stress has been suggested to be involved in human neurodegenerative diseases, such as Alzheimers disease, Parkinsons disease, and amyotrophic lateral sclerosis, as well as other disorders. Here we will discuss the neurotoxic effect of ER stress in these three major neurodegenerative diseases, and highlight current knowledge in this field that may reveal novel insight into disease mechanisms and help to design better therapies for these disorders.