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

  • Nature. 2000 Sep 7;407(6800):48-54. doi: 10.1038/35024009.
G Yu  1 ,  M Nishimura ,  S Arawaka ,  D Levitan ,  L Zhang ,  A Tandon ,  Y Q Song ,  E Rogaeva ,  F Chen ,  T Kawarai ,  A Supala ,  L Levesque ,  H Yu ,  D S Yang ,  E Holmes ,  P Milman ,  Y Liang ,  D M Zhang ,  D H Xu ,  C Sato ,  E Rogaev ,  M Smith ,  C Janus ,  Y Zhang ,  R Aebersold ,  L S Farrer ,  S Sorbi ,  A Bruni ,  P Fraser ,  P St George-Hyslop
Affiliations
  • 1. Centre for Research in Neurodegenerative Diseases, Toronto Western Hospital, and Department of Medicine (Neurology), University of Toronto, Ontario, Canada.
PMID: 10993067 DOI: 10.1038/35024009
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.