2000 Fiscal Year Final Research Report Summary
Cloning for presenilin cleaving enzyme
| Project/Area Number |
11670943
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Psychiatric science
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| Research Institution | Osaka University |
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Principal Investigator |
KUDO Takashi Graduate School of Medicine, Osaka University Lecturer, 医学系研究科, 講師 (10273632)
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| Co-Investigator(Kenkyū-buntansha) |
TANAKA Toshihisa Graduate School of Medicine, Osaka University Assistant Professor, 医学系研究科, 助手 (10294068)
NAKAMURA Yu Graduate School of Medicine, Osaka University Assistant Professor, 医学系研究科, 助手 (70291440)
TAKEDA Masatoshi Graduate School of Medicine, Osaka University Professor, 医学系研究科, 教授 (00179649)
IMAIZUMI Kazunori Medicen School, Osaka Univ., 医学系研究科, 講師
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| Project Period (FY) |
1999 – 2000
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| Keywords | Alzheimer disease / presenilin / endoplasmin reticulum / GRP 78 |
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| Research Abstract |
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.
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