title: Dissociated phenotypes in presenilin transgenic mice define functionally distinct gamma-secretases.
abstract: Gamma-secretase depends on presence of presenilins (PS), Nct, Aph-1, and PEN-2 within a core complex. This endoproteolytic activity cleaves within transmembrane domains of amyloid-beta precursor protein (APP) and Notch, and familial Alzheimer's disease (FAD) mutations in PS1 or PS2 genes shift APP cleavage from production of amyloid-beta (Abeta) 40 peptide to greater production of Abeta42. Although studies in PS1/PS2-deficient embryonic cells define overlapping activities for these proteins, in vivo complementation of PS1-deficient animals described here reveals an unexpected spectrum of activities dictated by PS1 and PS2 alleles. Unlike PS1 transgenes, wild-type PS2 transgenes expressed in the mouse CNS support little Abeta40 or Abeta42 production, and FAD PS2 alleles support robust production of only Abeta42. Although wild-type PS2 transgenes failed to rescue Notch-associated skeletal defects in PS1 hypomorphs, a "gained" competence in this regard was apparent for FAD alleles of PS2. The range of discrete and divergent processing activities in mice reconstituted with different PS genes and alleles argues against gamma-secretase being a single enzyme with intrinsically relaxed substrate and cleavage site specificities. Instead, our studies define functionally distinct gamma-secretase variants. We speculate that extrinsic components, in combination with core complexes, may tailor functional variants of this enzyme to their preferred substrates.
authors.affiliation: Centre for Research in Neurodegenerative Diseases, Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada M5S 3H2.
authors.forename: Peter
authors.initials: P
authors.lastname: Mastrangelo
authors.forename: Paul M
authors.initials: PM
authors.lastname: Mathews
authors.forename: M Azhar
authors.initials: MA
authors.lastname: Chishti
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Schmidt
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Gu
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Mazzella
authors.forename: Janaky
authors.initials: J
authors.lastname: Coomaraswamy
authors.forename: Patrick
authors.initials: P
authors.lastname: Horne
authors.forename: Bob
authors.initials: B
authors.lastname: Strome
authors.forename: Heather
authors.initials: H
authors.lastname: Pelly
authors.forename: Georges
authors.initials: G
authors.lastname: Levesque
authors.forename: Chris
authors.initials: C
authors.lastname: Ebeling
authors.forename: Ying
authors.initials: Y
authors.lastname: Jiang
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Nixon
authors.forename: Richard
authors.initials: R
authors.lastname: Rozmahel
authors.forename: Paul E
authors.initials: PE
authors.lastname: Fraser
authors.forename: Peter
authors.initials: P
authors.lastname: St George-Hyslop
authors.forename: George A
authors.initials: GA
authors.lastname: Carlson
authors.forename: David
authors.initials: D
authors.lastname: Westaway
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D001842:Bone and Bones / Q000002:abnormalities / Q000473:pathology; D010450:Endopeptidases; D006720:Homozygote; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D010446:Peptide Fragments / Q000378:metabolism; D010641:Phenotype; D053764:Presenilin-1; D053766:Presenilin-2
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; D010446:Peptide Fragments; D053764:Presenilin-1; D053766:Presenilin-2; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse