Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and betaAPP processing |
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| Authors: | Yu G Nishimura M Arawaka S Levitan D Zhang L Tandon A Song Y Q Rogaeva E Chen F Kawarai T Supala A Levesque L Yu H Yang D S Holmes E Milman P Liang Y Zhang D M Xu D H Sato C Rogaev E Smith M Janus C Zhang Y Aebersold R Farrer L S Sorbi S Bruni A Fraser P St George-Hyslop P |
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| Institution: | Centre for Research in Neurodegenerative Diseases, Toronto Western Hospital, and Department of Medicine (Neurology), University of Toronto, Ontario, Canada. |
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| Abstract: | Nicastrin, a transmembrane glycoprotein, forms high molecular weight complexes with presenilin 1 and presenilin 2. Suppression of nicastrin expression in Caenorhabditis elegans embryos induces a subset of notch/glp-1 phenotypes similar to those induced by simultaneous null mutations in both presenilin homologues of C. elegans (sel-12 and hop-1). Nicastrin also binds carboxy-terminal derivatives of beta-amyloid precursor protein (betaAPP), and modulates the production of the amyloid beta-peptide (A beta) from these derivatives. Missense mutations in a conserved hydrophilic domain of nicastrin increase A beta42 and A beta40 peptide secretion. Deletions in this domain inhibit A beta production. Nicastrin and presenilins are therefore likely to be functional components of a multimeric complex necessary for the intramembranous proteolysis of proteins such as Notch/GLP-1 and betaAPP. |
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