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Niemann-Pick disease type C1 is a sphingosine storage disease that causes deregulation of lysosomal calcium

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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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Figure 1: NPC1 lysosomal calcium homeostasis.
Figure 2: Abnormal lysosomal calcium is an early event during U18666A-induced NPC1 disease cellular phenotype.
Figure 3: Sphingosine specifically reduces lysosomal calcium.
Figure 4: Elevation of cytosolic calcium corrects NPC-mutant cellular phenotypes.
Figure 5: Increased survival and improved function in NPC1 mice treated with curcumin.
Figure 6: Curcumin-induced elevation in cytosolic calcium overcomes reduced lysosomal calcium and corrects endocytic transport in NPC1-null cells.

Change history

  • 05 August 2010

     In the version of this article initially published, one of the labels in Figure 5b was incorrect. The correct label for the mouse in the bottom panel should be Npc1−/− + curcumin 9 weeks. The error has been corrected in the HTML and PDF versions of the article.

References

  1. Vanier, M.T. & Millat, G. Niemann-Pick disease type C. Clin. Genet. 64, 269–281 (2003).

    Google Scholar 

  2. Ko, D.C., Gordon, M.D., Jin, J.Y. & Scott, M.P. Dynamic movements of organelles containing Niemann-Pick C1 protein: NPC1 involvement in late endocytic events. Mol. Biol. Cell 12, 601–614 (2001).

    Google Scholar 

  3. Liscum, L. Niemann-Pick type C mutations cause lipid traffic jam. Traffic 1, 218–225 (2000).

    Google Scholar 

  4. Davies, J.P., Chen, F.W. & Ioannou, Y.A. Transmembrane molecular pump activity of Niemann-Pick C1 protein. Science 290, 2295–2298 (2000).

    Google Scholar 

  5. Naureckiene, S. et al. Identification of HE1 as the second gene of Niemann-Pick C disease. Science 290, 2298–2301 (2000).

    Google Scholar 

  6. Babalola, J.O. et al. Development of an assay for the intermembrane transfer of cholesterol by Niemann-Pick C2 protein. Biol. Chem. 388, 617–626 (2007).

    Google Scholar 

  7. Butler, J.D., Vanier, M.T. & Pentchev, P.G. Niemann-Pick C disease: cystine and lipids accumulate in the murine model of this lysosomal cholesterol lipidosis. Biochem. Biophys. Res. Commun. 196, 154–159 (1993).

    Google Scholar 

  8. te Vruchte, D. et al. Accumulation of glycosphingolipids in Niemann-Pick C disease disrupts endosomal transport. J. Biol. Chem. 279, 26167–26175 (2004).

    Google Scholar 

  9. Patterson, M.C. & Platt, F. Therapy of Niemann-Pick disease, type C. Biochim. Biophys. Acta 1685, 77–82 (2004).

    Google Scholar 

  10. Patterson, M.C. et al. The effect of cholesterol-lowering agents on hepatic and plasma cholesterol in Niemann-Pick disease type C. Neurology 43, 61–64 (1993).

    Google Scholar 

  11. Erickson, R.P., Garver, W.S., Camargo, F., Hossain, G.S. & Heidenreich, R.A. Pharmacological and genetic modifications of somatic cholesterol do not substantially alter the course of CNS disease in Niemann-Pick C mice. J. Inherit. Metab. Dis. 23, 54–62 (2000).

    Google Scholar 

  12. Somers, K.L. et al. Effects of dietary cholesterol restriction in a feline model of Niemann-Pick type C disease. J. Inherit. Metab. Dis. 24, 427–436 (2001).

    Google Scholar 

  13. Lachmann, R.H. et al. Treatment with miglustat reverses the lipid-trafficking defect in Niemann-Pick disease type C. Neurobiol. Dis. 16, 654–658 (2004).

    Google Scholar 

  14. Patterson, M.C., Vecchio, D., Prady, H., Abel, L. & Wraith, J.E. Miglustat for treatment of Niemann-Pick C disease: a randomised controlled study. Lancet Neurol. 6, 765–772 (2007).

    Google Scholar 

  15. Ginzburg, L., Kacher, Y. & Futerman, A.H. The pathogenesis of glycosphingolipid storage disorders. Semin. Cell Dev. Biol. 15, 417–431 (2004).

    Google Scholar 

  16. Jeyakumar, M., Dwek, R.A., Butters, T.D. & Platt, F.M. Storage solutions: treating lysosomal disorders of the brain. Nat. Rev. Neurosci. 6, 713–725 (2005).

    Google Scholar 

  17. Christensen, K.A., Myers, J.T. & Swanson, J.A. pH-dependent regulation of lysosomal calcium in macrophages. J. Cell Sci. 115, 599–607 (2002).

    Google Scholar 

  18. Bach, G., Chen, C.S. & Pagano, R.E. Elevated lysosomal pH in mucolipidosis type IV cells. Clin. Chim. Acta 280, 173–179 (1999).

    Google Scholar 

  19. Parkesh, R. et al. Cell-permeant NAADP: A novel chemical tool enabling the study of Ca2+ signalling in intact cells. Cell Calcium 43, 531–538 (2008).

    Google Scholar 

  20. Galione, A. & Churchill, G.C. Interactions between calcium release pathways: multiple messengers and multiple stores. Cell Calcium 32, 343–354 (2002).

    Google Scholar 

  21. Churchill, G.C. et al. NAADP mobilizes Ca2+ from reserve granules, lysosome-related organelles, in sea urchin eggs. Cell 111, 703–708 (2002).

    Google Scholar 

  22. Piper, R.C. & Luzio, J.P. CUPpling calcium to lysosomal biogenesis. Trends Cell Biol. 14, 471–473 (2004).

    Google Scholar 

  23. Bilmen, J.G., Khan, S.Z., Javed, M.H. & Michelangeli, F. Inhibition of the SERCA Ca2+ pumps by curcumin. Curcumin putatively stabilizes the interaction between the nucleotide-binding and phosphorylation domains in the absence of ATP. Eur. J. Biochem. 268, 6318–6327 (2001).

    Google Scholar 

  24. Infante, R.E. et al. Purified NPC1 protein: II. Localization of sterol binding to a 240–amino acid soluble luminal loop. J. Biol. Chem. 283, 1064–1075 (2008).

    Google Scholar 

  25. Malathi, K. et al. Mutagenesis of the putative sterol-sensing domain of yeast Niemann Pick C–related protein reveals a primordial role in subcellular sphingolipid distribution. J. Cell Biol. 164, 547–556 (2004).

    Google Scholar 

  26. Sun, X. et al. Niemann-Pick C variant detection by altered sphingolipid trafficking and correlation with mutations within a specific domain of NPC1. Am. J. Hum. Genet. 68, 1361–1372 (2001).

    Google Scholar 

  27. Houben, E. et al. Differentiation-associated expression of ceramidase isoforms in cultured keratinocytes and epidermis. J. Lipid Res. 47, 1063–1070 (2006).

    Google Scholar 

  28. Kagedal, K., Zhao, M., Svensson, I. & Brunk, U.T. Sphingosine-induced apoptosis is dependent on lysosomal proteases. Biochem. J. 359, 335–343 (2001).

    Google Scholar 

  29. Kitatani, K., Idkowiak-Baldys, J. & Hannun, Y.A. The sphingolipid salvage pathway in ceramide metabolism and signaling. Cell Signal. 20, 1010–1018 (2008).

    Google Scholar 

  30. Tettamanti, G., Bassi, R., Viani, P. & Riboni, L. Salvage pathways in glycosphingolipid metabolism. Biochimie 85, 423–437 (2003).

    Google Scholar 

  31. Maceyka, M. et al. SphK1 and SphK2, sphingosine kinase isoenzymes with opposing functions in sphingolipid metabolism. J. Biol. Chem. 280, 37118–37129 (2005).

    Google Scholar 

  32. Ozbay, T., Rowan, A., Leon, A., Patel, P. & Sewer, M.B. Cyclic adenosine 5′-monophosphate–dependent sphingosine-1-phosphate biosynthesis induces human CYP17 gene transcription by activating cleavage of sterol regulatory element binding protein 1. Endocrinology 147, 1427–1437 (2006).

    Google Scholar 

  33. Pandol, S.J., Schoeffield-Payne, M.S., Gukovskaya, A.S. & Rutherford, R.E. Sphingosine regulates Ca2+-ATPase and reloading of intracellular Ca2+ stores in the pancreatic acinar cell. Biochim. Biophys. Acta 1195, 45–50 (1994).

    Google Scholar 

  34. Walter, M., Chen, F.W., Tamari, F., Wang, R. & Ioannou, Y.A. Endosomal lipid accumulation in NPC1 leads to inhibition of PKC, hypophosphorylation of vimentin and Rab9 entrapment. Biol. Cell published online, doi:10.1042/BC20070171 (6 August 2008).

  35. Garaschuk, O., Yaari, Y. & Konnerth, A. Release and sequestration of calcium by ryanodine-sensitive stores in rat hippocampal neurones. J. Physiol. (Lond.) 502, 13–30 (1997).

    Google Scholar 

  36. Deisz, R.A., Meske, V., Treiber-Held, S., Albert, F. & Ohm, T.G. Pathological cholesterol metabolism fails to modify electrophysiological properties of afflicted neurones in Niemann-Pick disease type C. Neuroscience 130, 867–873 (2005).

    Google Scholar 

  37. Lemons, R.M. & Thoene, J.G. Mediated calcium transport by isolated human fibroblast lysosomes. J. Biol. Chem. 266, 14378–14382 (1991).

    Google Scholar 

  38. Srinivas, S.P., Ong, A., Goon, L., Goon, L. & Bonanno, J.A. Lysosomal Ca2+ stores in bovine corneal endothelium. Invest. Ophthalmol. Vis. Sci. 43, 2341–2350 (2002).

    Google Scholar 

  39. Masson, M., Spezzatti, B., Chapman, J., Battisti, C. & Baumann, N. Calmodulin antagonists chlorpromazine and W-7 inhibit exogenous cholesterol esterification and sphingomyelinase activity in human skin fibroblast cultures. Similarities between drug-induced and Niemann-Pick type C lipidoses. J. Neurosci. Res. 31, 84–88 (1992).

    Google Scholar 

  40. Mayran, N., Parton, R.G. & Gruenberg, J. Annexin II regulates multivesicular endosome biogenesis in the degradation pathway of animal cells. EMBO J. 22, 3242–3253 (2003).

    Google Scholar 

  41. Ayala-Sanmartin, J., Henry, J.P. & Pradel, L.A. Cholesterol regulates membrane binding and aggregation by annexin 2 at submicromolar Ca2+ concentration. Biochim. Biophys. Acta 1510, 18–28 (2001).

    Google Scholar 

  42. Wu, Y.P., Mizugishi, K., Bektas, M., Sandhoff, R. & Proia, R.L. Sphingosine kinase 1/S1P receptor signaling axis controls glial proliferation in mice with Sandhoff disease. Hum. Mol. Genet. 17, 2257–2264 (2008).

    Google Scholar 

  43. Yamamoto, T. et al. Genotype-phenotype relationship of Niemann-Pick disease type C: a possible correlation between clinical onset and levels of NPC1 protein in isolated skin fibroblasts. J. Med. Genet. 37, 707–712 (2000).

    Google Scholar 

  44. Pelled, D., Sperling, O. & Zoref-Shani, E. Abnormal purine and pyrimidine nucleotide content in primary astroglia cultures from hypoxanthine-guanine phosphoribosyltransferase–deficient transgenic mice. J. Neurochem. 72, 1139–1145 (1999).

    Google Scholar 

  45. Rakovic, S. et al. An antagonist of cADP-ribose inhibits arrhythmogenic oscillations of intracellular Ca2+ in heart cells. J. Biol. Chem. 274, 17820–17827 (1999).

    Google Scholar 

  46. He, X., Dagan, A., Gatt, S. & Schuchman, E.H. Simultaneous quantitative analysis of ceramide and sphingosine in mouse blood by naphthalene-2,3-dicarboxyaldehyde derivatization after hydrolysis with ceramidase. Anal. Biochem. 340, 113–122 (2005).

    Google Scholar 

  47. Neville, D.C. et al. Analysis of fluorescently labeled glycosphingolipid-derived oligosaccharides following ceramide glycanase digestion and anthranilic acid labeling. Anal. Biochem. 331, 275–282 (2004).

    Google Scholar 

  48. Yamaji, A. et al. Lysenin, a novel sphingomyelin-specific binding protein. J. Biol. Chem. 273, 5300–5306 (1998).

    Google Scholar 

  49. Biwersi, J., Emans, N. & Verkman, A.S. Cystic fibrosis transmembrane conductance regulator activation stimulates endosome fusion in vivo. Proc. Natl. Acad. Sci. USA 93, 12484–12489 (1996).

    Google Scholar 

  50. Elliot-Smith, E. et al. Beneficial effects of substrate reduction therapy in a mouse model of GM1 gangliosidosis. Mol. Genet. Metab. 94, 204–211 (2008).

    Google Scholar 

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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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Correspondence to Emyr Lloyd-Evans or Frances M Platt.

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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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