期刊
NATURE MEDICINE
卷 14, 期 11, 页码 1247-1255出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.1876
关键词
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资金
- Biotechnology and Biological Sciences Research Council [BB/D012694/1] Funding Source: Medline
- NIDDK NIH HHS [NIHR01 DK54830] Funding Source: Medline
- Biotechnology and Biological Sciences Research Council [BB/D012694/1] Funding Source: researchfish
- BBSRC [BB/D012694/1] Funding Source: UKRI
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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