PMID- 10587643
OWN - NLM
STAT- MEDLINE
DCOM- 20000908
LR  - 20181130
IS  - 1465-7392 (Print)
IS  - 1465-7392 (Linking)
VI  - 1
IP  - 8
DP  - 1999 Dec
TI  - Presenilin-1 mutations downregulate the signalling pathway of the
      unfolded-protein response.
PG  - 479-85
AB  - 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.
FAU - Katayama, T
AU  - Katayama T
AD  - Department of Anatomy and Neuroscience, Graduate School of Medicine, Osaka
      University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
FAU - Imaizumi, K
AU  - Imaizumi K
FAU - Sato, N
AU  - Sato N
FAU - Miyoshi, K
AU  - Miyoshi K
FAU - Kudo, T
AU  - Kudo T
FAU - Hitomi, J
AU  - Hitomi J
FAU - Morihara, T
AU  - Morihara T
FAU - Yoneda, T
AU  - Yoneda T
FAU - Gomi, F
AU  - Gomi F
FAU - Mori, Y
AU  - Mori Y
FAU - Nakano, Y
AU  - Nakano Y
FAU - Takeda, J
AU  - Takeda J
FAU - Tsuda, T
AU  - Tsuda T
FAU - Itoyama, Y
AU  - Itoyama Y
FAU - Murayama, O
AU  - Murayama O
FAU - Takashima, A
AU  - Takashima A
FAU - St George-Hyslop, P
AU  - St George-Hyslop P
FAU - Takeda, M
AU  - Takeda M
FAU - Tohyama, M
AU  - Tohyama M
LA  - eng
PT  - Journal Article
PL  - England
TA  - Nat Cell Biol
JT  - Nature cell biology
JID - 100890575
RN  - 0 (Carrier Proteins)
RN  - 0 (HSP70 Heat-Shock Proteins)
RN  - 0 (Heat-Shock Proteins)
RN  - 0 (Membrane Proteins)
RN  - 0 (Molecular Chaperones)
RN  - 0 (PSEN1 protein, human)
RN  - 0 (Presenilin-1)
RN  - 0 (RNA, Messenger)
RN  - 0 (glucose-regulated proteins)
RN  - 11089-65-9 (Tunicamycin)
RN  - 37H9VM9WZL (Calcimycin)
RN  - EC 2.7.1.- (ERN2 protein, human)
RN  - EC 2.7.1.- (Ern2 protein, mouse)
RN  - EC 2.7.11.1 (Protein-Serine-Threonine Kinases)
RN  - EC 3.1.- (Endoribonucleases)
RN  - YCYIS6GADR (molecular chaperone GRP78)
SB  - IM
MH  - Alzheimer Disease/metabolism/pathology
MH  - Animals
MH  - Brain/metabolism/pathology
MH  - Calcimycin/pharmacology
MH  - Carrier Proteins/genetics/metabolism
MH  - Cell Death/drug effects
MH  - Cell Line
MH  - Endoplasmic Reticulum/drug effects/*metabolism
MH  - Endoribonucleases
MH  - HSP70 Heat-Shock Proteins/metabolism
MH  - *Heat-Shock Proteins
MH  - Humans
MH  - Intracellular Membranes/metabolism
MH  - Membrane Proteins/genetics/*metabolism
MH  - Mice
MH  - Mice, Transgenic
MH  - Molecular Chaperones/genetics/metabolism
MH  - Mutation/*genetics
MH  - Neuroblastoma
MH  - Neurons/drug effects/metabolism/pathology
MH  - Phosphorylation
MH  - Presenilin-1
MH  - Protein Binding
MH  - Protein Denaturation
MH  - *Protein Folding
MH  - Protein-Serine-Threonine Kinases/genetics/metabolism
MH  - RNA, Messenger/genetics/metabolism
MH  - *Signal Transduction/drug effects
MH  - Transfection
MH  - Tunicamycin/pharmacology
EDAT- 1999/12/10 09:00
MHDA- 2000/09/19 11:01
CRDT- 1999/12/10 09:00
PHST- 1999/12/10 09:00 [pubmed]
PHST- 2000/09/19 11:01 [medline]
PHST- 1999/12/10 09:00 [entrez]
AID - 10.1038/70265 [doi]
PST - ppublish
SO  - Nat Cell Biol. 1999 Dec;1(8):479-85. doi: 10.1038/70265.