PMID- 10497236
OWN - NLM
STAT- MEDLINE
DCOM- 19991102
LR  - 20210209
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 274
IP  - 40
DP  - 1999 Oct 1
TI  - A loss of function mutation of presenilin-2 interferes with amyloid beta-peptide 
      production and notch signaling.
PG  - 28669-73
AB  - Presenilin-1 (PS1) facilitates gamma-secretase cleavage of the beta-amyloid
      precursor protein and the intramembraneous cleavage of Notch1. Although
      Alzheimer's disease-associated mutations in the homologous presenilin (PS2) gene 
      elevate amyloid beta-peptide (Abeta42) production like PS1 mutations, here we
      demonstrate that a gene ablation of PS2 (unlike that of PS1) in mice does not
      result in a severe phenotype resembling that of Notch-ablated animals. To
      investigate the amyloidogenic function of PS2 more directly, we mutagenized a
      conserved aspartate at position 366 to alanine, because the corresponding residue
      of PS1 is known to be required for its amyloidogenic function. Cells expressing
      the PS2 D366A mutation exhibit significant deficits in proteolytic processing of 
      beta-amyloid precursor protein indicating a defect in gamma-secretase activity.
      The reduced gamma-secretase activity results in the almost complete inhibition of
      Abeta and p3 production in cells stably expressing PS2 D366A, whereas cells
      overexpressing the wild-type PS2 cDNA produce robust levels of Abeta and p3.
      Using highly sensitive in vivo assays, we demonstrate that the PS2 D366A mutation
      not only blocks gamma-secretase activity but also inactivates PS2 activity in
      Notch signaling by inhibiting the proteolytic release of the cytoplasmic Notch1
      domain. These data suggest that PS2 is functionally involved in Abeta production 
      and Notch signaling by facilitating similar proteolytic cleavages.
FAU - Steiner, H
AU  - Steiner H
AD  - Central Institute of Mental Health, Department of Molecular Biology, J5, 68159
      Mannheim, Germany.
FAU - Duff, K
AU  - Duff K
FAU - Capell, A
AU  - Capell A
FAU - Romig, H
AU  - Romig H
FAU - Grim, M G
AU  - Grim MG
FAU - Lincoln, S
AU  - Lincoln S
FAU - Hardy, J
AU  - Hardy J
FAU - Yu, X
AU  - Yu X
FAU - Picciano, M
AU  - Picciano M
FAU - Fechteler, K
AU  - Fechteler K
FAU - Citron, M
AU  - Citron M
FAU - Kopan, R
AU  - Kopan R
FAU - Pesold, B
AU  - Pesold B
FAU - Keck, S
AU  - Keck S
FAU - Baader, M
AU  - Baader M
FAU - Tomita, T
AU  - Tomita T
FAU - Iwatsubo, T
AU  - Iwatsubo T
FAU - Baumeister, R
AU  - Baumeister R
FAU - Haass, C
AU  - Haass C
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Amyloid beta-Peptides)
RN  - 0 (Membrane Proteins)
RN  - 0 (PSEN2 protein, human)
RN  - 0 (Peptide Fragments)
RN  - 0 (Presenilin-2)
RN  - 0 (Receptors, Notch)
RN  - 0 (amyloid beta-protein (1-42))
SB  - IM
MH  - Amyloid beta-Peptides/*antagonists & inhibitors/biosynthesis
MH  - Animals
MH  - Animals, Genetically Modified
MH  - Cell Line
MH  - Humans
MH  - Hydrolysis
MH  - Membrane Proteins/*genetics/*metabolism/physiology
MH  - Mice
MH  - Mice, Knockout
MH  - *Mutation
MH  - Peptide Fragments/*antagonists & inhibitors/biosynthesis
MH  - Presenilin-2
MH  - Receptors, Notch
MH  - Signal Transduction/*genetics
EDAT- 1999/09/25 00:00
MHDA- 1999/09/25 00:01
CRDT- 1999/09/25 00:00
PHST- 1999/09/25 00:00 [pubmed]
PHST- 1999/09/25 00:01 [medline]
PHST- 1999/09/25 00:00 [entrez]
AID - 10.1074/jbc.274.40.28669 [doi]
AID - S0021-9258(19)52099-3 [pii]
PST - ppublish
SO  - J Biol Chem. 1999 Oct 1;274(40):28669-73. doi: 10.1074/jbc.274.40.28669.