Article abstract
Nature Medicine 14, 1247 - 1255 (2008)
Published online: 26 October 2008 | doi:10.1038/nm.1876
Niemann-Pick disease type C1 is a sphingosine storage disease that causes deregulation of lysosomal calcium
Emyr Lloyd-Evans1, Anthony J Morgan1, Xingxuan He2, David A Smith1, Elena Elliot-Smith1, Daniel J Sillence3, Grant C Churchill1, Edward H Schuchman2, Antony Galione1 & Frances M Platt1
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.
- Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK.
- Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, 1425 Madison Avenue, New York, New York 10029, USA.
- Present address: Leicester School of Pharmacy, De Montfort University, The Gateway, Leicester LE1 9BH, UK.
Correspondence to: Emyr Lloyd-Evans1 e-mail: emyr.lloyd-evans@pharm.ox.ac.uk
Correspondence to: Frances M Platt1 e-mail: frances.platt@pharm.ox.ac.uk
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