Mutation of the conserved N-terminal cysteine (Cys92) of human presenilin 1 causes increased A beta42 secretion in mammalian cells but impaired Notch/lin-12 signalling in C. elegans.
The presenilin proteins are involved in the proteolytic processing of transmembrane proteins such as Notch/lin-12 and the beta-amyloid precursor protein (betaAPP). Mutation of a conserved cysteine (Cys60Ser) in the C. elegans presenilin sel-12 has a loss-of-function effect on Notch/lin-12 processing similar to that of null mutations in sel-12. In contrast, in mammalian cells, most missense mutations increase gamma-secretase cleavage of betaAPP. We report here that mutation of this conserved cysteine (Cys92Ser) in human presenilin 1 confers a loss-of-function effect in C. elegans, but causes increased A beta42 secretion in mammalian cells. These data suggest that the role of presenilins in Notch/lin-12 signalling and betaAPP processing are either separately regulated activities or independent activities of the presenilins.
Zhang
D M
DM
Centre for Research in Neurodegenerative Diseases, Department of Medicine (Neurology), The University Health Network, University of Toronto, Ontario, Canada.
Levitan
D
D
Yu
G
G
Nishimura
M
M
Chen
F
F
Tandon
A
A
Kawarai
T
T
Arawaka
S
S
Supala
A
A
Song
Y Q
YQ
Rogaeva
E
E
Liang
Y
Y
Holmes
E
E
Milman
P
P
Sato
C
C
Zhang
L
L
St George-Hyslop
P
P
D016229:Amyloid beta-Peptides / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics* / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins; D003545:Cysteine / Q000235:genetics*; D015801:Helminth Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D020125:Mutation, Missense / Q000502:physiology; D010446:Peptide Fragments / Q000235:genetics* / Q000378:metabolism; D017354:Point Mutation / Q000235:genetics; D053764:Presenilin-1; D017434:Protein Structure, Tertiary / Q000235:genetics; D051880:Receptors, Notch; D015398:Signal Transduction / Q000235:genetics
D016229:Amyloid beta-Peptides; D029742:Caenorhabditis elegans Proteins; D015801:Helminth Proteins; C082460:Lin-12 protein, C elegans; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D051880:Receptors, Notch; C075222:amyloid beta-protein (1-42); D003545:Cysteine