Protein from neuronal death by regulation ER stress response.

据报道，多种神经退行性疾病与内质网（ER）应激有关。为了制定这些疾病的治疗策略，ER应激反应的整个方面都应该弄清楚。在本研究中，我们证明了以下问题：1）我们确定了一种新的ER应激传感器BBF2H7，它在缺血脑的神经元中表达。这些分子在响应ER应激的跨膜结构域处被切割。BBF2H7的N端片段被转位到细胞核中并激活靶基因的转录。2）在暴露于ER应激的神经元中，被认为是具有胞质内容物的双膜结构的自噬体的形成被促进。自噬的紊乱使细胞对ER应激变得脆弱，这表明自噬在ER应激后的细胞存活中起重要作用。3）在筛选诱导ER介导的伴侣蛋白BiP的化合物时，我们鉴定了BiP诱导剂X（BIX）。用BIX预处理神经母细胞瘤细胞减少了由ER应激诱导的细胞死亡。4）在原代培养的神经元中，ER应激感受器IRE1、PERK和ATF6均存在于索马和树突的ER中，BiP和磷酸化eIF2a被诱导表达。这些结果表明，树突中的内质网能够对内质网应激作出反应，并保持蛋白质质量控制的能力。

Various neurodegenerative diseases are reported to be associated with be endoplasmic reticulum (ER) stress. To develop therapeutic strategies for these diseases, the whole aspects of ER stress response should be made clear. In the present study, we demonstrated the following issues ;1) We identified a novel ER stress sensor BBF2H7, which is expressed in neurons of ischemic brains. The molecules are cleaved at the transmembrane domain in response to ER stress. N-terminal fragments of cleaved BBF2H7 are translocated into the nucleus and activates the transcription of target genes.2) The formation of autophagosomes that are recognized as the double membrane structure with cytoplasmic contents was promoted in the neurons that were exposed to ER stress. Disturbance of autophagy rendered cells vulnerable to ER stress, suggesting that autophagy plays important roles in cell survival after ER stress.3) In screening for compounds that induce the ER-mediated chaperone BiP, we identified BiP Inducer X (BIX). Pretreatment of neuroblastoma cells with BIX reduced cell death induced by ER stress. Intracerebroventricular pretreatment with BIX reduced the area of infarction due to focal cerebral ischemia in mice, suggesting that it may be a potential therapeutic agent for cerebral diseases caused by ER stress.4) We demonstrated that ER stress sensors, IRE1, PERK, and ATF6 exist in the ER of both soma and dendrites in primary cultured neurons, and that BiP and phosphoryrated eIF2a are induced. These results indicate that the ER in dendrites could respond to ER stress and retain the capacity of protein quality control.