Alleles at the Nicastrin locus modify presenilin 1- deficiency phenotype.
Presenilin 1 (PS1), presenilin 2, and nicastrin form high molecular weight complexes that are necessary for the endoproteolysis of several type 1 transmembrane proteins, including amyloid precursor protein (APP) and the Notch receptor, by apparently similar mechanisms. The cleavage of the Notch receptor at the "S3-site" releases a C-terminal cytoplasmic fragment (Notch intracellular domain) that acts as the intracellular transduction molecule for Notch activation. Missense mutations in the presenilins cause familial Alzheimer's disease by augmenting the "gamma-secretase" cleavage of APP and overproducing one of the proteolytic derivatives, the Abeta peptide. Null mutations in PS1 inhibit both gamma-secretase cleavage of APP and S3-site cleavage of the Notch receptor. Mice lacking PS1 function have defective Notch signaling and die perinatally with severe skeletal and brain deformities. We report here that a genetic modifier on mouse distal chromosome 1, coinciding with the locus containing Nicastrin, influences presenilin-mediated Notch S3-site cleavage and the resultant Notch phenotype without affecting presenilin-mediated APP gamma-site cleavage. Two missense substitutions of residues conserved among vertebrates have been identified in nicastrin. These results indicate that Notch S3-site cleavage and APP gamma-site cleavage are distinct presenilin-dependent processes and support a functional interaction between nicastrin and presenilins in vertebrates. The dissociation of Notch S3-site and APP gamma-site cleavage activities will facilitate development of gamma-secretase inhibitors for treatment of Alzheimer's disease.
Rozmahel
Richard
R
Center for Research in Neurodegenerative Diseases, Department of Pharmacology, University of Toronto, Toronto, ON, Canada M5S 1A8. Rozmahel@uab.edu
Mount
Howard T J
HT
Chen
Fusheng
F
Nguyen
Van
V
Huang
Jean
J
Erdebil
Serap
S
Liauw
Jennifer
J
Yu
Gang
G
Hasegawa
Hiroshe
H
Gu
YongJun
Y
Song
You-Qiang
YQ
Schmidt
Stephen D
SD
Nixon
Ralph A
RA
Mathews
Paul M
PM
Bergeron
Catherine
C
Fraser
Paul
P
Westaway
David
D
St George-Hyslop
Peter
P
D000483:Alleles; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D001665:Binding Sites; D001947:Breeding; D002874:Chromosome Mapping; D010450:Endopeptidases / Q000378:metabolism; D005260:Female; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010446:Peptide Fragments / Q000378:metabolism; D010641:Phenotype; D053764:Presenilin-1; D051880:Receptors, Notch; D013131:Spine / Q000002:abnormalities*
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D010446:Peptide Fragments; D053764:Presenilin-1; D051880:Receptors, Notch; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C413604:nicastrin protein; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse