A molecular chaperone inducer protects neurons from ER stress
A molecular chaperone inducer protects neurons from ER stress
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DOI：
10.1038/sj.cdd.4402276
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发表时间：
2008-02-01
影响因子：
12.4
通讯作者：
Takeda, M.
中科院分区：
文献类型：
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作者：
Kudo, T.;Kanemoto, S.;Takeda, M.
内质网（ER）应激反应是一种防御系统，用于处理内质网管内未折叠蛋白的积累。最近的报道表明内质网应激参与了一些神经退行性疾病脑缺血的病理过程。在筛选诱导er介导的伴侣蛋白BiP（免疫球蛋白重链蛋白）/GRP78 （78 kDa葡萄糖调节蛋白）的化合物时，我们发现了BiP诱导剂X （BIX）。BIX优先诱导GRP94 （94 kDa葡萄糖调节蛋白）、钙网蛋白和C/EBP同源蛋白诱导BiP。BIX对mRNA的诱导是通过激活BiP基因上游的内质网应激反应元件，通过ATF6（转录因子6）途径。BIX预处理神经母细胞瘤细胞可减少内质网引起的细胞死亡，脑室内BIX预处理可减少小鼠局灶性脑缺血引起的梗死面积。在bix处理的小鼠半暗区，内质网应激诱导的凋亡被抑制，导致细胞数量减少。综上所述，BIX诱导BiP预防内质网应激导致的神经元死亡，可能是内质网应激引起的脑疾病的潜在治疗剂。
The endoplasmic reticulum (ER) stress response is a defense system for dealing with the accumulation of unfolded proteins the ER lumen. Recent reports have shown that ER stress is involved in the pathology of some neurodegenerative diseases cerebral ischemia. In a screen for compounds that induce the ER-mediated chaperone BiP (immunoglobulin heavy-chain protein)/GRP78 (78 kDa glucose-regulated protein), we identified BiP inducer X (BIX). BIX preferentially induced BiP with inductions of GRP94 (94 kDa glucose-regulated protein), calreticulin, and C/EBP homologous protein. The induction of mRNA by BIX was mediated by activation of ER stress response elements upstream of the BiP gene, through the ATF6 (transcription factor 6) pathway. Pretreatment of neuroblastoma cells with BIX reduced cell death induced by ER Intracerebroventricular pretreatment with BIX reduced the area of infarction due to focal cerebral ischemia in mice. In penumbra of BIX-treated mice, ER stress-induced apoptosis was suppressed, leading to a reduction in the number of cells. Considering these results together, it appears that BIX induces BiP to prevent neuronal death by ER stress, suggesting it may be a potential therapeutic agent for cerebral diseases caused by ER stress.