Characterization of mouse Ire1α:: cloning, mRNA localization in the brain and functional analysis in a neural cell line
Characterization of mouse Ire1α:: cloning, mRNA localization in the brain and functional analysis in a neural cell line
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DOI：
10.1016/s0169-328x(00)00243-6
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发表时间：
2000-12-28
期刊：
影响因子：
--
通讯作者：
Tohyama, M
中科院分区：
文献类型：
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作者：
Miyoshi, K;Katayama, T;Tohyama, M
酵母中的一种内质网（ER）相关蛋白。Irelp被认为启动未折叠蛋白反应（UPR），其负责在应激条件下ER中的蛋白质折叠。已经鉴定了Irelp的两种哺乳动物同源物，Ire 1 α和Irelp。我们以前曾报道过家族性阿尔茨海默病相关的早老素-1变异体通过影响Ire 1 α的磷酸化而下调UPR的信号通路。在本研究中，我们克隆了Ire 1 alpha的小鼠同源物，用于产生转基因小鼠。Ire 1 α在所有检测的小鼠组织中普遍表达，并且优先在小鼠脑中的神经元细胞中表达。这使我们研究ER应激条件下UPR下调对神经细胞存活的影响。形态学和生物化学研究使用的小鼠Ire 1 α的显性阴性形式揭示了ER应激引起的细胞死亡可归因于细胞凋亡，并且UPR的下调增强了小鼠神经母细胞瘤细胞系Neuro 2a中的细胞凋亡过程。我们的研究结果表明，转基因小鼠，如显性阴性转基因小鼠提供了进一步了解阿尔茨海默病和其他神经退行性疾病的致病机制。(C)2000爱思唯尔科技有限公司。保留所有权利。
In yeast, an endoplasmic reticulum (ER)-associated protein. Irelp, is believed to initiate the unfolded protein response (UPR), that is responsible for protein folding in the ER under stressed conditions. Two mammalian homologs of Irelp have been identified, Ire1 alpha and Irelp. We have previously reported that familial Alzheimer's disease linked presenilin-1 variants downregulate the signaling pathway of the UPR by affecting the phosphorylation of Ire1 alpha. In the present study, we cloned the mouse homolog of Ire1 alpha for generating genetically modified mice. Ire1 alpha was ubiquitously expressed in all mouse tissues examined, and was expressed preferentially in neuronal cells in mouse brain. This led us to investigate the effects of the downregulation of the UPR on the survival of neuronal cells under conditions of ER stress. Morphological and biochemical studies using a dominant-negative form of mouse Ire1 alpha have revealed that cell death caused by ER stress can be attributed to apoptosis, and that the downregulation of the UPR enhances the apoptotic process in the mouse neuroblastoma cell Line, Neuro2a. Our results indicate that genetically modified mice such as transgenic mice with a dominant-negative provide further understanding of the pathogenic mechanisms of Alzheimer's disease and other neurodegenerative disorders. (C) 2000 Elsevier Science B.V. All rights reserved.