title: Impaired dynamics of the late endosome/lysosome compartment in human Niemann-Pick type C skin fibroblasts carrying mutation in NPC1 gene.
abstract: The Niemann-Pick type C (NPC) disease is characterized by accumulation of lipids within the late endosome/lysosome (LE/LY) compartment as a result of dysfunctions of the NPC1 or NPC2 proteins and an altered distribution and/or functioning of proteins involved in the regulation of membrane dynamics. In our previous report we isolated membranes of the LE/LY compartment from NPC L1 skin fibroblasts with a mutation in the NPC1 gene (exon 8, R348X) and showed that annexin A6 (AnxA6) may contribute to the impaired dynamics of these membranes in a cholesterol-dependent manner and therefore to the overnormative storage of cholesterol. In this report we show that the LE/LY fraction isolated from NPC L1 cells is characterized by a 4-fold enrichment in cholesterol, 2.5-fold in sphingomyelin and 2-fold in saturated fatty acids. As a result, the fluidity of LE/LY membranes isolated from NPC L1 cells is greatly reduced in comparison to control ones. We conclude that modified lipid composition and properties of this compartment may affect distribution and function of proteins implicated in cellular membrane dynamics. As a consequence, the backward vesicular transport of cholesterol from the LE/LY compartment to the Golgi apparatus, endoplasmic reticulum and finally to plasma membrane is impaired.
authors.affiliation: Department of Biochemistry, Nencki Institute of Experimental Biology, Polish Academy of Sciences, PL-02093 Warsaw, Poland.
authors.forename: Malgorzata E
authors.initials: ME
authors.lastname: Sztolsztener
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Dobrzyn
authors.forename: Slawomir
authors.initials: S
authors.lastname: Pikula
authors.forename: Anna
authors.initials: A
authors.lastname: Tylki-Szymanska
authors.forename: Joanna
authors.initials: J
authors.lastname: Bandorowicz-Pikula
mesh_terms: D000328:Adult; D017317:Annexin A6 / Q000378:metabolism; D001692:Biological Transport; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002458:Cell Fractionation; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002675:Child, Preschool; D002784:Cholesterol / Q000378:metabolism; D002855:Chromatography, Thin Layer / Q000379:methods; D004721:Endoplasmic Reticulum / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism*; D005227:Fatty Acids / Q000032:analysis; D005260:Female; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D050356:Lipid Metabolism; D008246:Lysophospholipids / Q000032:analysis / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism*; D008560:Membrane Fluidity; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D050178:Monoglycerides / Q000032:analysis / Q000378:metabolism; D009154:Mutation; D000077296:Niemann-Pick C1 Protein; D052556:Niemann-Pick Disease, Type C / Q000235:genetics*; D012867:Skin / Q000166:cytology; D013109:Sphingomyelins / Q000032:analysis
chemical_list: D017317:Annexin A6; D002352:Carrier Proteins; D005227:Fatty Acids; D047908:Intracellular Signaling Peptides and Proteins; D008246:Lysophospholipids; D008562:Membrane Glycoproteins; D050178:Monoglycerides; C106881:NPC1 protein, human; D000077296:Niemann-Pick C1 Protein; D013109:Sphingomyelins; C012786:bis(monoacylglyceryl)phosphate; D002784:Cholesterol