Presenilin-1 mutations downregulate the signalling pathway of the unfolded-protein response.
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.
Katayama
T
T
Department of Anatomy and Neuroscience, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Imaizumi
K
K
Sato
N
N
Miyoshi
K
K
Kudo
T
T
Hitomi
J
J
Morihara
T
T
Yoneda
T
T
Gomi
F
F
Mori
Y
Y
Nakano
Y
Y
Takeda
J
J
Tsuda
T
T
Itoyama
Y
Y
Murayama
O
O
Takashima
A
A
St George-Hyslop
P
P
Takeda
M
M
Tohyama
M
M
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D000001:Calcimycin / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D004722:Endoribonucleases; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006360:Heat-Shock Proteins; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D009447:Neuroblastoma; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D053764:Presenilin-1; D011485:Protein Binding; D011489:Protein Denaturation; D017510:Protein Folding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D014415:Tunicamycin / Q000494:pharmacology
D002352:Carrier Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; D018840:HSP70 Heat-Shock Proteins; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D008565:Membrane Proteins; D018832:Molecular Chaperones; C508853:PSEN1 protein, human; D053764:Presenilin-1; D012333:RNA, Messenger; C018551:glucose-regulated proteins; D014415:Tunicamycin; D000001:Calcimycin; C403982:ERN2 protein, human; C486556:Ern2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases