Alleles at the Nicastrin Locus Modify Presenilin 1-Deficiency Phenotype

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 99; no. 22; pp. 14452 - 14457
• Main Authors: Rozmahel, Richard, Howard T.J. Mount, Chen, Fusheng, Nguyen, Van, Huang, Jean, Erdebil, Serap, Liauw, Jennifer, Yu, Gang, Hasegawa, Hiroshe, Gu, YongJun, Song, You-Qiang, Schmidt, Stephen D., Nixon, Ralph A., Mathews, Paul M., Bergeron, Catherine, Fraser, Paul, Westaway, David, St George-Hyslop, Peter
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 29.10.2002; National Acad Sciences
• Subjects: Alleles; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - metabolism; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Binding Sites; Biological Sciences; Breeding; Chromosome Mapping; Chromosomes; DNA; Endopeptidases - metabolism; Female; Genes; Genetic loci; Genomes; Male; Membrane Glycoproteins - genetics; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Mutation; Neurology; Peptide Fragments - metabolism; Phenotype; Phenotypes; Presenilin-1; Presenilins; Proteins; Receptors, Notch; Spine; Spine - abnormalities
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.222413999

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 "γ-secretase" cleavage of APP and overproducing one of the proteolytic derivatives, the Aβ peptide. Null mutations in PS1 inhibit both γ-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 γ-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 γ-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 γ-site cleavage activities will facilitate development of γ-secretase inhibitors for treatment of Alzheimer's disease.