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应激有关。为了制定治疗这些疾病的策略，内质网应激反应的各个方面都应该清楚。在本研究中，我们论证了以下问题；1)我们发现了一种新的内质网应激传感器BBF2H7，它在缺血脑的神经元中表达。分子在响应内质网应激的跨膜区域被劈裂。被切割的BBF2H7的n端片段易位到细胞核中，激活靶基因的转录。2)内质网应激促进了神经元自噬体的形成，自噬体被认为是具有胞质内容物的双膜结构。自噬的干扰使细胞易受内质网应激，提示自噬在内质网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BiP的化合物时，我们鉴定了BiP诱导剂X （BIX）。BIX预处理神经母细胞瘤细胞可减少内质网应激引起的细胞死亡。脑室内预处理BIX可减少小鼠局灶性脑缺血引起的梗死面积，提示其可能是内质网应激引起的脑疾病的潜在治疗剂。4)我们证明了内质网应激传感器IRE1、PERK和ATF6存在于原代培养的神经元体细胞和树突的内质网中，并诱导了BiP和磷酸化的eIF2a。这些结果表明，树突内的内质网能够对内质网胁迫作出反应，并保持对蛋白质质量的控制能力。

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.