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Presenilin-1 mutations downregulate the signalling pathway of the unfolded-protein response
T Katayama1, K Imaizumi, N Sato
1Department of Anatomy and Neuroscience, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Insights
Missense mutations in the presenilin-1 (PS1) gene linked to familial Alzheimer's disease disrupt the unfolded-protein response (UPR). This disruption, involving IRE1 and GRP78, increases cellular vulnerability to endoplasmic reticulum stress.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Missense mutations in the human presenilin-1 (PS1) gene cause early-onset familial Alzheimer's disease (FAD).
- FAD-linked PS1 variants are known to affect amyloid precursor protein processing and increase apoptosis vulnerability.
- The precise mechanisms underlying these effects remain unclear.
Purpose of the Study:
- To investigate the impact of PS1 mutations on the unfolded-protein response (UPR) pathway.
- To elucidate the role of PS1 in endoplasmic reticulum (ER) stress response.
- To determine if GRP78/Bip levels are affected by PS1 mutations and if this relates to ER stress.
Main Methods:
- Analysis of UPR signaling in cells with PS1 mutations.
- Measurement of GRP78/Bip expression in relation to PS1 variants.
- Investigation of IRE1 function in PS1 mutant cells.
- Functional rescue experiments involving GRP78 overexpression.
Main Results:
- PS1 mutations were found to disrupt the UPR pathway.
- Expression of GRP78/Bip, an ER chaperone, was decreased in cells with PS1 mutations.
- Disturbed IRE1 function was identified as a cause for UPR downregulation.
- Overexpression of GRP78 restored resistance to ER stress in PS1 mutant cells.
Conclusions:
- Mutations in PS1 alter UPR signaling, leading to reduced GRP78/Bip expression.
- This alteration increases cellular vulnerability to endoplasmic reticulum stress.
- The findings suggest a novel mechanism by which PS1 mutations contribute to Alzheimer's disease pathogenesis.
Abstract:
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.