Katayama T, Imaizumi K, Sato N, Miyoshi K, Kudo T, Hitomi J, Morihara T, Yoneda T, Gomi F, Mori Y, Nakano Y, Takeda J, Tsuda T, Itoyama Y, Murayama O, Takashima A, St George-Hyslop P, Takeda M, Tohyama M
Department of Anatomy and Neuroscience, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Nat Cell Biol. 1999 Dec;1(8):479-85. doi: 10.1038/70265.
Missense mutations in the human presenilin-1 (PS1) gene, which is found on chromosome 14, cause early-onset familial Alzheimer's disease (FAD). FAD-linked PS1 variants alter proteolytic processing of the amyloid precursor protein and cause an increase in vulnerability to apoptosis induced by various cell stresses. However, the mechanisms responsible for these phenomena are not clear. Here we report that mutations in PS1 affect the unfolded-protein response (UPR), which responds to the increased amount of unfolded proteins that accumulate in the endoplasmic reticulum (ER) under conditions that cause ER stress. PS1 mutations also lead to decreased expression of GRP78/Bip, a molecular chaperone, present in the ER, that can enable protein folding. Interestingly, GRP78 levels are reduced in the brains of Alzheimer's disease patients. The downregulation of UPR signalling by PS1 mutations is caused by disturbed function of IRE1, which is the proximal sensor of conditions in the ER lumen. Overexpression of GRP78 in neuroblastoma cells bearing PS1 mutants almost completely restores resistance to ER stress to the level of cells expressing wild-type PS1. These results show that mutations in PS1 may increase vulnerability to ER stress by altering the UPR signalling pathway.
人类早老素1（PS1）基因位于14号染色体上，该基因的错义突变会导致早发性家族性阿尔茨海默病（FAD）。与FAD相关的PS1变体改变了淀粉样前体蛋白的蛋白水解过程，并导致细胞在各种应激条件下对凋亡的易感性增加。然而，导致这些现象的机制尚不清楚。在此我们报告，PS1中的突变会影响未折叠蛋白反应（UPR），UPR是对在内质网（ER）应激条件下在内质网中积累的未折叠蛋白数量增加作出反应的机制。PS1突变还会导致内质网中一种名为GRP78/Bip的分子伴侣的表达减少，该分子伴侣能够促进蛋白质折叠。有趣的是，阿尔茨海默病患者大脑中的GRP78水平降低。PS1突变导致的UPR信号下调是由IRE1功能紊乱引起的，IRE1是内质网腔环境的近端传感器。在携带PS1突变体的神经母细胞瘤细胞中过表达GRP78几乎完全将内质网应激抗性恢复到表达野生型PS1的细胞水平。这些结果表明，PS1中的突变可能通过改变UPR信号通路增加对内质网应激的易感性。
