title: Cessation of rapid late endosomal tubulovesicular trafficking in Niemann-Pick type C1 disease.
abstract: Niemann-Pick type C1 (NPC1) disease results from a defect in the NPC1 protein and is characterized by a pathological accumulation of cholesterol and glycolipids in endocytic organelles. We followed the biosynthesis and trafficking of NPC1 with the use of a functional green fluorescent protein-fused NPC1. Newly synthesized NPC1 is exported from the endoplasmic reticulum and requires transit through the Golgi before it is targeted to late endosomes. NPC1-containing late endosomes then move by a dynamic process involving tubulation and fission, followed by rapid retrograde and anterograde migration along microtubules. Cell fusion studies with normal and mutant NPC1 cells show that exchange of contents between late endosomes and lysosomes depends upon ongoing tubulovesicular late endocytic trafficking. In turn, rapid endosomal tubular movement requires an intact NPC1 sterol-sensing domain and is retarded by an elevated endosomal cholesterol content. We conclude that the neuropathology and cellular lysosomal lipid accumulation in NPC1 disease results, at least in part, from striking defects in late endosomal tubulovesicular trafficking.
authors: Lipid Cell Biology Section and Cell Biochemistry Section, National Institute of Diabetes and Digestive and Kidney Diseases, and Developmental and Metabolic Neurology Branch, National Institutes of Health, Bethesda, MD 20892, USA.
authors: M
authors: M
authors: Zhang
authors: N K
authors: NK
authors: Dwyer
authors: D C
authors: DC
authors: Love
authors: A
authors: A
authors: Cooney
authors: M
authors: M
authors: Comly
authors: E
authors: E
authors: Neufeld
authors: P G
authors: PG
authors: Pentchev
authors: E J
authors: EJ
authors: Blanchette-Mackie
authors: J A
authors: JA
authors: Hanover
mesh_terms: D000818:Animals; D015153:Blotting, Western; D016466:CHO Cells; D002352:Carrier Proteins / Q000378:metabolism; D002451:Cell Compartmentation; D002784:Cholesterol / Q000378:metabolism; D006224:Cricetinae; D004705:Endocytosis; D004721:Endoplasmic Reticulum / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism*; D006056:Golgi Apparatus / Q000378:metabolism; D049452:Green Fluorescent Proteins; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008164:Luminescent Proteins / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D008856:Microscopy, Fluorescence; D000077296:Niemann-Pick C1 Protein; D009542:Niemann-Pick Diseases / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008164:Luminescent Proteins; D008562:Membrane Glycoproteins; C106881:NPC1 protein, human; D000077296:Niemann-Pick C1 Protein; D049452:Green Fluorescent Proteins; D002784:Cholesterol