The Niemann-Pick C1 protein resides in a vesicular compartment linked to retrograde transport of multiple lysosomal cargo

Niemann-Pick C disease (NP-C) is a neurovisceral lysosomal storage disorder . A variety of studies have highlighted defective sterol trafficking from l ysosomes in NP-C cells. However, the heterogeneous nature of additional acc umulating metabolites suggests that the cellular lesion may involve a more generalized block in retrograde lysosomal trafficking. Immunocytochemical studies in fibroblasts reveal that the NPC1 gene product resides in a novel set of lysosome-associated membrane protein-2 (LAMPS)()/ mannose g-phosphate receptor(-) vesicles that can be distinguished from cholesterol-enriched LAMP2(+) lysosomes, Drugs that block sterol transport out of lysosomes also redistribute NPC1 to cholesterol-laden lysosomes. Ste rol relocation from lysosomes in cultured human fibroblasts can be blocked at 21 degrees C, consistent with vesicle-mediated transfer. These findings suggest that NPC1(+) vesicles may transiently interact with lysosomes to fa cilitate sterol relocation. Independent of defective sterol trafficking, NP-C fibroblasts are also defi cient in vesicle-mediated clearance of endocytosed [C-14]sucrose. Compartme ntal modeling of the observed [C-14]sucrose clearance data targets the traf ficking defect caused by mutations in NPC1 to an endocytic compartment prox imal to lysosomes, Low density lipoprotein uptake by normal cells retards r etrograde transport of [C-14]sucrose through this same kinetic compartment, further suggesting that it may contain the sterol-sensing NPC1 protein. We conclude that a distinctive organelle containing NPC1 mediates retrograd e lysosomal transport of endocytosed cargo that is not restricted to sterol .