title: Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo.
abstract: The majority of early-onset cases of familial Alzheimer's disease (FAD) are linked to mutations in two related genes, PS1 and PS2, located on chromosome 14 and 1, respectively. Using two highly specific antibodies against nonoverlapping epitopes of the PS1-encoded polypeptide, termed presenilin 1 (PS1), we document that the preponderant PS1-related species that accumulate in cultured mammalian cells, and in the brains of rodents, primates, and humans are approximately 27-28 kDa N-terminal and approximately 16-17 kDa C-terminal derivatives. Notably, a FAD-linked PS1 variant that lacks exon 9 is not subject to endoproteolytic cleavage. In brains of transgenic mice expressing human PS1, approximately 17 kDa and approximately 27 kDa PS1 derivatives accumulate to saturable levels, and at approximately 1:1 stoichiometry, independent of transgene-derived mRNA. We conclude that PS1 is subject to endoproteolytic processing in vivo.
authors: Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors: G
authors: G
authors: Thinakaran
authors: D R
authors: DR
authors: Borchelt
authors: M K
authors: MK
authors: Lee
authors: H H
authors: HH
authors: Slunt
authors: L
authors: L
authors: Spitzer
authors: G
authors: G
authors: Kim
authors: T
authors: T
authors: Ratovitsky
authors: F
authors: F
authors: Davenport
authors: C
authors: C
authors: Nordstedt
authors: M
authors: M
authors: Seeger
authors: J
authors: J
authors: Hardy
authors: A I
authors: AI
authors: Levey
authors: S E
authors: SE
authors: Gandy
authors: N A
authors: NA
authors: Jenkins
authors: N G
authors: NG
authors: Copeland
authors: D L
authors: DL
authors: Price
authors: S S
authors: SS
authors: Sisodia
mesh_terms: D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D015335:Molecular Probes / Q000235:genetics; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000378:metabolism; D010447:Peptide Hydrolases / Q000378:metabolism*; D053764:Presenilin-1
chemical_list: D008565:Membrane Proteins; D015335:Molecular Probes; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D010447:Peptide Hydrolases