PMID- 10545183
OWN - NLM
STAT- MEDLINE
DCOM- 19991222
LR  - 20190613
IS  - 0006-2960 (Print)
IS  - 0006-2960 (Linking)
VI  - 38
IP  - 44
DP  - 1999 Nov 2
TI  - Amyloidogenic function of the Alzheimer's disease-associated presenilin 1 in the 
      absence of endoproteolysis.
PG  - 14600-5
AB  - Alzheimer's disease (AD) is characterized by the invariant accumulation of senile
      plaques predominantly composed of the pathologically relevant 42-amino acid
      amyloid beta-peptide (Abeta42). The presenilin (PS) proteins play a key role in
      Abeta generation. FAD-associated mutations in PS1 and PS2 enhance the production 
      of Abeta42, and PS1 is required for physiological Abeta production, since a gene 
      knockout of PS1 and dominant negative mutations of PS1 abolish Abeta generation. 
      PS proteins undergo endoproteolytic processing, and current evidence indicates
      that fragment formation may be required for the amyloidogenic function of PS. We 
      have now determined the sequence requirements for endoproteolysis of PS1.
      Mutagenizing amino acids at the previously determined major cleavage site (amino 
      acid 298) had no effect on PS1 endoproteolysis. In contrast, mutations or
      deletions at the additional cleavage site around amino acid 292 blocked
      endoproteolysis. The uncleavable PS1 derivatives accumulated as full-length
      proteins and replaced the endogenous PS1 proteins. In contrast to the previously 
      described aspartate mutations within transmembrane domains 6 and 7, the uncleaved
      PS1 variants do not act as dominant negative inhibitors of Abeta production.
      Moreover, when a FAD-associated mutation (M146L) was combined with a mutation
      blocking endoproteolysis, Abeta42 production still reached pathological levels.
      These data therefore demonstrate that endoproteolysis of presenilins is not an
      absolute prerequisite for the amyloidogenic function of PS1. These data also show
      that accumulation of the PS1 holoprotein is not associated with the pathological 
      activity of PS1 mutations as suggested previously.
FAU - Steiner, H
AU  - Steiner H
AD  - Department of Molecular Biology, Central Institute of Mental Health, J5, 68159
      Mannheim, Germany.
FAU - Romig, H
AU  - Romig H
FAU - Pesold, B
AU  - Pesold B
FAU - Philipp, U
AU  - Philipp U
FAU - Baader, M
AU  - Baader M
FAU - Citron, M
AU  - Citron M
FAU - Loetscher, H
AU  - Loetscher H
FAU - Jacobsen, H
AU  - Jacobsen H
FAU - Haass, C
AU  - Haass C
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Biochemistry
JT  - Biochemistry
JID - 0370623
RN  - 0 (Amyloid beta-Peptides)
RN  - 0 (DNA, Complementary)
RN  - 0 (Membrane Proteins)
RN  - 0 (PSEN1 protein, human)
RN  - 0 (Presenilin-1)
RN  - EC 3.4.- (Endopeptidases)
SB  - IM
MH  - Alzheimer Disease/genetics/*metabolism
MH  - Amino Acid Sequence
MH  - Amyloid beta-Peptides/*biosynthesis
MH  - Binding Sites/genetics
MH  - Cell Line
MH  - DNA, Complementary/genetics
MH  - Endopeptidases/metabolism
MH  - Humans
MH  - Membrane Proteins/chemistry/genetics/*metabolism
MH  - Mutation
MH  - Point Mutation
MH  - Presenilin-1
MH  - Transfection
EDAT- 1999/11/05 00:00
MHDA- 1999/11/05 00:01
CRDT- 1999/11/05 00:00
PHST- 1999/11/05 00:00 [pubmed]
PHST- 1999/11/05 00:01 [medline]
PHST- 1999/11/05 00:00 [entrez]
AID - bi9914210 [pii]
AID - 10.1021/bi9914210 [doi]
PST - ppublish
SO  - Biochemistry. 1999 Nov 2;38(44):14600-5. doi: 10.1021/bi9914210.