The Caenorhabditis elegans IMPAS gene, imp-2, is essential for development and is functionally distinct from related presenilins

doi:10.1073/pnas.0406462101

The Caenorhabditis elegans IMPAS gene, imp-2, is essential for development and is functionally distinct from related presenilins

^*Department of Psychiatry, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, 303 Belmont Street, Worcester, MA 01604; ^†Laboratory of Molecular Brain Genetics, Research Center of Mental Health, Russian Academy of Medical Sciences, Zagorodnoe Shosse 2/2, Moscow 113152, Russia; ^‡Institute of Molecular Genetics, Russian Academy of Sciences, Kurchatov Square 2, Moscow 123182, Russia; ^§Department of Pathology and Laboratory Medicine, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854; ^¶Program in Molecular Medicine, University of Massachusetts Medical School, Howard Hughes Medical Institute, 373 Plantation Street, Worcester, MA 01605; and ^∥A. N. Belozersky Institute of Physical and Chemical Biology, Lomonosov Moscow State University, Moscow 119992, Russia

Communicated by S. J. Singer, University of California at San Diego, La Jolla, CA, September 2, 2004 (received for review June 25, 2004)

Abstract

Presenilins (PSs) are required for Notch signaling in the development of vertebrates and invertebrates. Mutations in human PS1 and PS2 homologs are a cause of familial Alzheimer's disease (AD). The function of the recently identified ancient family of IMPAS proteins (IMP/SPP/PSH) homologous to PSs is not yet known. We show here that, unlike PSs, IMPs (orthologous C. elegans Ce-imp-2 and human hIMP1/SPP) do not promote Notch (C. elegans lin-12,glp-1) proteolysis or signaling. The knock-down of Ce-imp-2 leads to embryonic death and an abnormal molting phenotype in Caenorhabditis elegans. The molting defect induced by Ce-imp-2 deficiency was mimicked by depleting cholesterol or disrupting Ce-lrp-1 and suppressed, in part, by expression of the Ce-lrp-1 derivate. C. elegans lrp-1 is a homolog of mammalian megalin, lipoprotein receptor-related protein (LRP) receptors essential for cholesterol and lipoprotein endocytosis and signaling. These data suggest that IMPs are functionally distinct from related PSs and implicate IMPs as critical regulators of development that may potentially interact with the lipid-lipoprotein receptor-mediated pathway.

Footnotes

↵ ** To whom correspondence should be addressed. E-mail: evgeny.rogaev{at}umassmed.edu.
Author contributions: C.C.M. and E.I.R. designed research; A.P.G., Y.K.M., and M.C.S. performed research; A.P.G., Y.K.M., C.C.M., and E.I.R. analyzed data; and E.I.R. wrote the paper.
Abbreviations: AD, Alzheimer's disease; ISC, incomplete shedding of cuticle; PS, presenilin; dsRNA, double-stranded RNA; RNAi, RNA interference; LRP, lipoprotein receptor-related protein.
↵ †† Rogaev, E. I., Grigorenko, A., Ryazanskaya, N., Sherbatich, T., Molyaka, Y., Korovaitseva, G. I. & Dvoryanchikov G. (2001) Sixth Human Genome Meeting, April 19-22, 2001, Edinburgh, N101, p. 28 (abstr.).