title: A model for niemann-pick type C disease in the nematode Caenorhabditis elegans.
abstract: Niemann-Pick type C (NP-C) disease is a progressive neurodegenerative disorder characterized by the inappropriate accumulation of unesterified cholesterol in lysosomes [1]. NP-C patients show various defects including hepatosplenomegaly, ataxia, dystonia and dementia. Most cases of NP-C are associated with inactivating mutations of the NPC1 gene [2], which encodes a protein implicated in the retrograde transport of sterols and other cargo from lysosomes [3]. Furthermore, localization of the NPC1 protein to lysosomal/endosomal compartments is essential for proper transport [4]. To create a model of NP-C disease in a simple, genetically tractable organism, we generated deletion mutations in two Caenorhabditis elegans homologs of the human NPC1 gene, designated npc-1 and npc-2. Animals mutant for npc-1 developed slowly, laid eggs prematurely, and were hypersensitive to cholesterol deprivation. Furthermore, npc-1; npc-2 double-mutant animals inappropriately formed dauer larvae under favorable growth conditions. These phenotypes in C. elegans provide a model system for both genetic and chemical suppressor screening that could identify promising drug targets and leads for NP-C disease.
authors.affiliation: NemaPharm Group, Axys Pharmaceuticals, Exelixis Incorporated, South San Francisco, 94080, USA. msym@exelixis.com
authors.forename: M
authors.initials: M
authors.lastname: Sym
authors.forename: M
authors.initials: M
authors.lastname: Basson
authors.forename: C
authors.initials: C
authors.lastname: Johnson
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017173:Caenorhabditis elegans / Q000196:embryology / Q000378:metabolism / Q000502:physiology; D002352:Carrier Proteins; D002784:Cholesterol / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D008969:Molecular Sequence Data; D016296:Mutagenesis; D000077296:Niemann-Pick C1 Protein; D009542:Niemann-Pick Diseases; D010058:Oviposition / Q000502:physiology; D011506:Proteins / Q000235:genetics / Q000502:physiology*
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; C106881:NPC1 protein, human; D000077296:Niemann-Pick C1 Protein; D011506:Proteins; D002784:Cholesterol