Linked Life Data

16644737

Source:http://linkedlifedata.com/resource/pubmed/id/16644737

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
26
pubmed:dateCreated
2006-6-26
pubmed:abstractText
Niemann-Pick type C disease is an autosomal recessive disorder that leads to massive accumulation of cholesterol and glycosphingolipids in late endosomes and lysosomes. To understand how cholesterol accumulation influences late endosome function, we investigated the effect of elevated cholesterol on Rab9-dependent export of mannose 6-phosphate receptors from this compartment. Endogenous Rab9 levels were elevated 1.8-fold in Niemann-Pick type C cells relative to wild type cells, and its half-life increased 1.6-fold, suggesting that Rab9 accumulation is caused by impaired protein turnover. Reduced Rab9 degradation was accompanied by stabilization on endosome membranes, as shown by a reduction in the capacity of Rab9 for guanine nucleotide dissociation inhibitor-mediated extraction from Niemann-Pick type C membranes. Cholesterol appeared to stabilize Rab9 directly, as liposomes loaded with prenylated Rab9 showed decreased extractability with increasing cholesterol content. Rab9 is likely sequestered in an inactive form on Niemann-Pick type C membranes, as cation-dependent mannose 6-phosphate receptors were missorted to the lysosome for degradation, a process that was reversed by overexpression of GFP-tagged Rab9. In addition to using primary fibroblasts isolated from Niemann-Pick type C patients, RNA interference was utilized to recapitulate the disease phenotype in cultured cells, greatly facilitating the analysis of cholesterol accumulation and late endosome function. We conclude that cholesterol contributes directly to the sequestration of Rab9 on Niemann-Pick type C cell membranes, which in turn, disrupts mannose 6-phosphate receptor trafficking.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
30
pubmed:volume
281
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
17890-9
pubmed:dateRevised
2007-11-15
pubmed:meshHeading
pubmed-meshheading:16644737-Animals, pubmed-meshheading:16644737-Biological Transport, pubmed-meshheading:16644737-Carrier Proteins, pubmed-meshheading:16644737-Cholesterol, pubmed-meshheading:16644737-Endosomes, pubmed-meshheading:16644737-Fibroblasts, pubmed-meshheading:16644737-Glycosphingolipids, pubmed-meshheading:16644737-HeLa Cells, pubmed-meshheading:16644737-Humans, pubmed-meshheading:16644737-Insects, pubmed-meshheading:16644737-Intracellular Membranes, pubmed-meshheading:16644737-Membrane Glycoproteins, pubmed-meshheading:16644737-Niemann-Pick Diseases, pubmed-meshheading:16644737-Phenotype, pubmed-meshheading:16644737-Protein Prenylation, pubmed-meshheading:16644737-Protein Transport, pubmed-meshheading:16644737-Receptor, IGF Type 2, pubmed-meshheading:16644737-rab GTP-Binding Proteins
pubmed:year
2006
pubmed:articleTitle
Cholesterol accumulation sequesters Rab9 and disrupts late endosome function in NPC1-deficient cells.
pubmed:affiliation
Department of Biochemistry, Stanford University School of Medicine, 279 Campus Drive, Stanford, CA 94305-5307, USA.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural