Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and βAPP processing

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 β-amyloid precursor protein (βAPP), and modulates the production of the amyloid β-peptide (Aβ) from these derivatives. Missense mutations in a conserved hydrophilic domain of nicastrin increase Aβ 42 and Aβ 40 peptide secretion. Deletions in this domain inhibit Aβ 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 βAPP.