内质网应激后未折叠蛋白反应在神经退行性疾病发病机制中的作用  

Pathogenic Role of UPR(Unfolded Protein Response) Among Hereditary Leukoencephalopathy and Neurodegenerative Disorders After Endoplasmic Reticulum Stress

作　　者：陈娜[1] 代丽芳[1] 姜玉武[1] 吴晔[1] 

机构地区：[1]北京大学第一医院儿科,北京100034

出　　处：《生物化学与生物物理进展》2012年第8期764-770,共7页Progress In Biochemistry and Biophysics

基　　金：国家自然科学基金(81171065);教育部新世纪优秀人才支持计划资助项目~~

摘　　要：内质网(endoplasmic reticulum,ER)负责蛋白质的正确折叠.当ER受到干扰,细胞内未折叠或错误折叠蛋白蓄积增多,引发ER应激,激活未折叠蛋白反应(UPR)来改变细胞的转录翻译水平,其目的是为了增加ER的蛋白质折叠能力、减轻细胞的损伤.然而,持续的ER应激会使细胞走向凋亡.UPR由3条内质网跨膜受体介导,分别是PERK(PKR-likeendoplasmic reticulum kinase)、ATF6(activating transcription factor6)以及IRE1(inositol requiring enzyme 1).首先激活的PERK通过将真核翻译起始因子2α(eIF2α)磷酸化来减少下游蛋白质的翻译,而磷酸化的eIF2α促使ATF4(activating transcriptionfactor4)以及一些下游分子的翻译.随后激活的ATF6以及IRE1共同参与ER应激.目前ER应激与一些神经退行性疾病发病机制的关联研究主要集中在阿尔茨海默病、帕金森病、白质消融性白质脑病、佩梅病、腓骨肌萎缩症以及CAG三核苷酸重复所致的亨廷顿病、脊髓小脑共济失调等.Endoplasmic reticulum （ER） is the protein-folding compartment. When the aggregation of unfolded or misfolded protein in the ER lumen excesses its folding capacity, unfolded protein response （UPR） and ER-associated protein degradation （ERAD） would be activated to eliminate the overload of nascent protein. However, the persistent ER stress would trigger apoptosis pathway and lead to cell death. There exist three pathways in the UPR process, which are mediated by three membrane receptors： PERK, ATF6 or IRE1 respectively. The first activated PERK would down regulates the protein synthesis through the phosphorylation of eukaryotic initiation factor （elF） 2a （eIF2a） and activate the upstream open reading frame. ATF6 and IRE1 also make the contribution to UPR. Up to now, the most studied neurodegenerative diseases that related to ER stresses are Alzheimer＇s disease, Parkinson＇s disease, Vanishing White Matter disease, Pelizaeus-Merzbacher disease, Charcot-Marie-Tooth disease and CAG triplet repeat diseases （as Huntington＇s disease and Spinocerebellar ataxia）.

关 键 词：内质网应激 未折叠蛋白反应 神经退行性疾病 遗传性白质脑病 

分 类 号：R74[医药卫生—神经病学与精神病学]