The Caenorhabditis elegans IMPAS Gene, imp-2, Is Essential for Development and Is Functionally Distinct from Related Presenilins

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...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2004-10, Vol.101 (41), p.14955-14960
Main Authors: Grigorenko, Anastasia P., Moliaka, Yuri K., Soto, Martha C., Mello, Craig C., Rogaev, Evgeny I., Singer, S. J.
Format: Article
Language:English
Subjects:
Alzheimer's disease
Animal cuticle
Animals
Biological Sciences
Caenorhabditis elegans
Caenorhabditis elegans - genetics
Caenorhabditis elegans Proteins - genetics
Cholesterols
Cloning, Molecular
Double stranded RNA
Endopeptidases - genetics
Gene expression regulation
Gene Expression Regulation, Developmental - genetics
Genes
HEK293 cells
Larval development
Membrane Proteins - genetics
Molting
Mutation
Phenotypes
Presenilins
Proteins
Recombinant Proteins - metabolism
RNA Interference
RNA, Double-Stranded - genetics
Worms
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0406462101