Nature Cell Biology
2, 205 - 211 (2000)
Published online: 3 March 2000; | doi:10.1038/35008626
Presenilin-1 differentially facilitates endoproteolysis of the  -amyloid
precursor protein and NotchAnja Capell1, 2, Harald Steiner1, 2, Helmut Romig3, Simone Keck1, 4, Miriam Baader1, 4, Melissa G. Grim6, Ralf Baumeister6
& Christian Haass11
Adolf Butenandt-Institute, Department of Biochemistry,
Laboratory for Alzheimer's Disease Research, Ludwig-Maximilians-University
, 80336 Munich, Germany
chaass@pbm.med.uni-muenchen.de
3
Boehringer Ingelheim KG, CNS Research,
55216 Ingelheim, Germany
6
Gene Center, Ludwig-Maximilians-University,
81377 Munich, Germany
4
Present address: Central Institute of Mental Health,
Department of Molecular Biology, J5, 68159 Mannheim
, Germany
2
These authors contributed equally to this work Mutations in the presenilin-1 (PS1) gene are associated with
Alzheimer's disease and cause increased secretion of the neurotoxic
amyloid- peptide (A). Critical intramembraneous aspartates
at residues 257 and 385 are required for the function of PS1 protein. Here
we investigate the biological function of a naturally occurring PS1 splice
variant (PS1  exon 8), which lacks the critical aspartate 257. Cell
lines that stably express PS1 exon 8 or a PS1 protein in which aspartate
residue 257 is mutated secrete significant levels of A, whereas A
generation is severely reduced in cells transfected with PS1 containing a
mutation of aspartate 385. In contrast, endoproteolytic processing of Notch
is almost completely inhibited in cell lines expressing any of the PS1 variants
that lack one of the critical aspartates. These data indicate that PS1 may
differentially facilitate  -secretase-mediated generation of A and
endoproteolysis of Notch.
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