Abstract
Niemann-Pick type C1 (NPC1) disease is a neurodegenerative lysosomal storage disorder caused by mutations in the acidic compartment (which we define as the late endosome and the lysosome) protein, NPC1. The function of NPC1 is unknown, but when it is dysfunctional, sphingosine, glycosphingolipids, sphingomyelin and cholesterol accumulate. We have found that NPC1-mutant cells have a large reduction in the acidic compartment calcium store compared to wild-type cells. Chelating luminal endocytic calcium in normal cells with high-affinity Rhod-dextran induced an NPC disease cellular phenotype. In a drug-induced NPC disease cellular model, sphingosine storage in the acidic compartment led to calcium depletion in these organelles, which then resulted in cholesterol, sphingomyelin and glycosphingolipid storage in these compartments. Sphingosine storage is therefore an initiating factor in NPC1 disease pathogenesis that causes altered calcium homeostasis, leading to the secondary storage of sphingolipids and cholesterol. This unique calcium phenotype represents a new target for therapeutic intervention, as elevation of cytosolic calcium with curcumin normalized NPC1 disease cellular phenotypes and prolonged survival of the NPC1 mouse.
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Acknowledgements
NPC1-mutant CHO cells (CT43) and controls (RA25) were a gift from T.Y. Chang (Dartmouth Medical School). Npc1−/− and Npc1+/+ mice were a gift from R. Lachmann (University of Cambridge). Magipix and Magigraph software were developed and distributed by R. Jacob (Kings College London). E.L.-E. was supported by grants from the Ara Parseghian Medical Research Foundation and Birth Defects Foundation Newlife. A.J.M. was supported by the Wellcome Trust, UK. X.H. was supported by NIHR01 DK54830. D.A.S. was supported by the National Niemann-Pick Disease Foundation USA. E.E.-S. was supported by the Glycobiology Institute, Oxford University. D.J.S. was supported by the Ara Parseghian Medical Research Foundation. We thank D. Jelfs and J. Freeman for expert technical assistance. We are indebted to the UK Niemann-Pick Disease Group for their interest and support of this research.
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E.L.-E., F.M.P., A.J.M. and A.G. devised and/or performed the experiments. E.H.S. and X.H. carried out sphingosine and S1P analysis, D.A.S. and E.E.-S. carried out behavioral analysis, D.J.S. and G.C.C. provided methods and reagents, and E.L.-E. and F.M.P. wrote the manuscript.
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Lloyd-Evans, E., Morgan, A., He, X. et al. Niemann-Pick disease type C1 is a sphingosine storage disease that causes deregulation of lysosomal calcium. Nat Med 14, 1247–1255 (2008). https://doi.org/10.1038/nm.1876
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DOI: https://doi.org/10.1038/nm.1876
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