Cloning for presenilin cleaving enzyme

人类早老素-1（PS1）基因（位于14号染色体上）的错配突变导致早发性家族性阿尔茨海默病（FAD）。FAD-连接的PS1变体改变淀粉样前体蛋白的蛋白水解加工，并导致各种细胞应激诱导的细胞凋亡的脆弱性增加。然而，造成这些现象的机制尚不清楚。在这里，我们报告说，PS1的突变影响未折叠蛋白反应（UPR），这响应于在内质网（ER）中积累的未折叠蛋白的量增加的条件下，导致ER应激。PS1突变还导致GRP 78/Bip的表达降低，GRP 78/Bip是一种存在于ER中的分子伴侣，可以使蛋白质折叠。有趣的是，GRP 78水平在阿尔茨海默病患者的大脑中降低。PS1突变引起的UPR信号转导的下调是由IRE 1的功能紊乱引起的，IRE 1是ER腔中条件的近端传感器。GRP 78在神经母细胞瘤细胞中的过表达使PS1突变体对ER应激的抗性几乎完全恢复到表达野生型PS1的细胞的水平。这些结果表明，PS1的突变可能会通过改变UPR信号通路增加对ER应激的脆弱性。

Missenes 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 me reduced in the brain 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.