Cessation of rapid late endosomal tubulovesicular trafficking in Niemann-Pick type C1 disease

Niemann-Pick type C1 (NPC1) disease results from a defect in the NPC1 prote in and is characterized by a pathological accumulation of cholesterol and g lycolipids in endocytic organelles. We followed the biosynthesis and traffi cking 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 t ubulation and fission, followed by rapid retrograde and anterograde migrati on along microtubules. Cell fusion studies with normal and mutant NPC1 cell s show that exchange of contents between late endosomes and lysosomes depen ds upon ongoing tubulovesicular late endocytic trafficking. In turn, rapid endosomal tubular movement requires an intact NPC1 sterol-sensing domain an d is retarded by an elevated endosomal cholesterol content. We conclude tha t the neuropathology and cellular lysosomal lipid accumulation in NPC1 dise ase results, at least in part, from striking defects in late endosomal tubu lovesicular trafficking.