1. Centre for Research in Neurodegenerative Diseases; The University Health Network (Toronto Western Hospital); and Departments of Medicine (Neurology) and Medical Biophysics, University of Toronto, Tanz Neuroscience Building, 6 Queen's Park Crescent West, Toronto, Ontario, M5S 3H2, Canada
2. Department of CNS and Cardiovascular Research, Schering Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033-0539 , USA
3. Molecular Biotechnology, University of Washington, Seattle, Washington 98195-7730 , USA
4. Genetics Program, Boston University School of Medicine, 80 East Concord Street, Boston , Massachusetts 02118-2394, USA
5. Department of Neurology, University of Florence, viale Morgagni 65, Florence 50134, Italy
6. Centro Regionale di Neurogenetica, USL 6, Lamezia Terme 88046, Italy
7. These authors contributed equally to this work

Correspondence to: Peter St George-Hyslop¹ Correspondence and requests for materials should be addressed to P.St G.-H. (e-mail: Email: p.hyslop@utoronto.ca).

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 -amyloid precursor protein (APP), and modulates the production of the amyloid -peptide (A) from these derivatives. Missense mutations in a conserved hydrophilic domain of nicastrin increase A₄₂ and A₄₀ peptide secretion. Deletions in this domain inhibit A 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 APP.