Alleles at the Nicastrin locus modify presenilin 1-deficiency phenotype

Richard Rozmahel, Howard T J Mount, Fusheng Chen, Van Nguyen, Jean Huang, Serap Erdebil, Jennifer Liauw, Gang Yu, Hiroshe Hasegawa, Yongjun Gu, You Qiang Song, Stephen D. Schmidt, Ralph A. Nixon, Paul M. Mathews, Catherine Bergeron, Paul Fraser, David Westaway, Peter St. George-Hyslop

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17 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)14452-14457
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume99
Issue number22
DOIs
StatePublished - Oct 29 2002

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    Rozmahel, R., Mount, H. T. J., Chen, F., Nguyen, V., Huang, J., Erdebil, S., Liauw, J., Yu, G., Hasegawa, H., Gu, Y., Song, Y. Q., Schmidt, S. D., Nixon, R. A., Mathews, P. M., Bergeron, C., Fraser, P., Westaway, D., & St. George-Hyslop, P. (2002). Alleles at the Nicastrin locus modify presenilin 1-deficiency phenotype. Proceedings of the National Academy of Sciences of the United States of America, 99(22), 14452-14457. https://doi.org/10.1073/pnas.222413999