Dissociated phenotypes in presenilin transgenic mice define functionally distinct gamma-secretases.
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.
Mastrangelo
Peter
P
Centre for Research in Neurodegenerative Diseases, Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada M5S 3H2.
Mathews
Paul M
PM
Chishti
M Azhar
MA
Schmidt
Stephen D
SD
Gu
Yongjun
Y
Yang
Jing
J
Mazzella
Matthew J
MJ
Coomaraswamy
Janaky
J
Horne
Patrick
P
Strome
Bob
B
Pelly
Heather
H
Levesque
Georges
G
Ebeling
Chris
C
Jiang
Ying
Y
Nixon
Ralph A
RA
Rozmahel
Richard
R
Fraser
Paul E
PE
St George-Hyslop
Peter
P
Carlson
George A
GA
Westaway
David
D
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
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