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Cholesterol in Niemann–Pick Type C disease

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Cholesterol Binding and Cholesterol Transport Proteins:

Part of the book series: Subcellular Biochemistry ((SCBI,volume 51))

Abstract

Niemann-Pick Type C (NPC) disease is associated with accumulation of cholesterol and other lipids in late endosomes/lysosomes in virtually every organ; however, neurodegeneration represents the fatal cause for the disease. Genetic analysis has identified loss-of-function mutations in NPC1 and NPC2 genes as the molecular triggers for the disease. Although the precise function of these proteins has not yet been clarified, recent research suggests that they orchestrate cholesterol efflux from late endosomes/lysosomes. NPC protein deficits result in impairment in intracellular cholesterol trafficking and dysregulation of cholesterol biosynthesis. Disruption of cholesterol homeostasis is also associated with deregulation of autophagic activity and early-onset neuroinflammation, which may contribute to the pathogenesis of NPC disease. This chapter reviews recent achievements in the investigation of disruption of cholesterol homeostasis-induced neurodegeneration in NPC disease, and provides new insight for developing a potential therapeutic strategy for this disorder.

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Abbreviations

GABA:

gamma-Aminobutyric acid

GD2:

disialoganglioside

LDL:

low density lipoprotein

NPC:

Niemann-Pick Type C

References

  • Ahmad, I., Lope-Piedrafita, S., Bi, X., Hicks, C., Yao, Y., Yu, C., Chaitkin, E., Howison, C. M., Weberg, L., Trouard, T. P., Erickson, R. P., 2005, Allopregnanolone treatment, both as a single injection or repetitively, delays demyelination and enhances survival of Niemann-Pick C mice. J. Neurosci. Res. 82: 811–821

    CAS  PubMed  Google Scholar 

  • Auer, I. A., Schmidt, M. L., Lee, V. M., Curry, B., Suzuki, K., Shin, R. W., Pentchev, P. G., Carstea, E. D., Trojanowski, J. Q., 1995, Paired helical filament tau (PHFtau) in Niemann-Pick type C disease is similar to PHFtau in Alzheimer’s disease. Acta Neuropathol. 90: 547–551

    CAS  PubMed  Google Scholar 

  • Baudry, M., Yao, Y., Simmons, D., Liu, J., Bi, X., 2003, Postnatal development of inflammation in a murine model of Niemann-Pick type C disease: immunohistochemical observations of microglia and astroglia. Exp. Neurol. 184: 887–903

    CAS  PubMed  Google Scholar 

  • Beltroy, E. P., Richardson, J. A., Horton, J. D., Turley, S. D., Dietschy, J. M., 2005, Cholesterol accumulation and liver cell death in mice with Niemann-Pick type C disease. Hepatology 42: 886–893

    CAS  PubMed  Google Scholar 

  • Berger, A. C., Salazar, G., Styers, M. L., Newell-Litwa, K. A., Werner, E., Maue, R. A., Corbett, A. H., Faundez, V., 2007, The subcellular localization of the Niemann-Pick Type C proteins depends on the adaptor complex AP-3. J. Cell Sci. 120: 3640–3652

    CAS  PubMed  Google Scholar 

  • Bi, X., Liao, G., 2007, Autophagic-lysosomal dysfunction and neurodegeneration in Niemann-Pick Type C mice: lipid starvation or indigestion? Autophagy 3: 646–648

    CAS  PubMed  Google Scholar 

  • Bi, X., Liu, J., Yao, Y., Baudry, M., Lynch, G., 2005, Deregulation of the phosphatidylinositol-3 kinase signaling cascade is associated with neurodegeneration in Npc1-/- mouse brain. Am. J. Pathol. 167: 1081–1092

    CAS  PubMed  Google Scholar 

  • Bookout, A. L., Jeong, Y., Downes, M., Yu, R. T., Evans, R. M., Mangelsdorf, D. J., 2006, Anatomical profiling of nuclear receptor expression reveals a hierarchical transcriptional network. Cell 126: 789–799

    CAS  PubMed  Google Scholar 

  • Boyles, J. K., Pitas, R. E., Wilson, E., Mahley, R. W., Taylor, J. M., 1985, Apolipoprotein E associated with astrocytic glia of the central nervous system and with nonmyelinating glia of the peripheral nervous system. J. Clin. Invest. 76: 1501–1513

    CAS  PubMed  Google Scholar 

  • Brecht, W. J., Harris, F. M., Chang, S., Tesseur, I., Yu, G. Q., Xu, Q., Dee Fish, J., Wyss-Coray, T., Buttini, M., Mucke, L., Mahley, R. W., Huang, Y., 2004, Neuron-specific apolipoprotein e4 proteolysis is associated with increased tau phosphorylation in brains of transgenic mice. J. Neurosci. 24: 2527–2534

    CAS  PubMed  Google Scholar 

  • Burns, M., Gaynor, K., Olm, V., Mercken, M., LaFrancois, J., Wang, L., Mathews, P. M., Noble, W., Matsuoka, Y., Duff, K., 2003, Presenilin redistribution associated with aberrant cholesterol transport enhances beta-amyloid production in vivo. J. Neurosci. 23: 5645–5649

    CAS  PubMed  Google Scholar 

  • Carstea, E. D., Morris, J. A., Coleman, K. G., Loftus, S. K., Zhang, D., Cummings, C., Gu, J., Rosenfeld, M. A., Pavan, W. J., Krizman, D. B., Nagle, J., Polymeropoulos, M. H., Sturley, S. L., Ioannou, Y. A., Higgins, M. E., Comly, M., Cooney, A., Brown, A., Kaneski, C. R., Blanchette-Mackie, E. J., Dwyer, N. K., Neufeld, E. B., Chang, T. Y., Liscum, L., Strauss, J. F., 3rd, Ohno, K., Zeigler, M., Carmi, R., Sokol, J., Markie, D., O’Neill, R. R., van Diggelen, O. P., Elleder, M., Patterson, M. C., Brady, R. O., Vanier, M. T., Pentchev, P. G., Tagle, D. A., 1997, Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeostasis. Science 277: 228–231

    CAS  PubMed  Google Scholar 

  • Cheng, J., Ohsaki, Y., Tauchi-Sato, K., Fujita, A., Fujimoto, T., 2006, Cholesterol depletion induces autophagy. Biochem. Biophys. Res. Commun. 351: 246–252

    CAS  PubMed  Google Scholar 

  • Cheruku, S. R., Xu, Z., Dutia, R., Lobel, P., Storch, J., 2006, Mechanism of cholesterol transfer from the Niemann-Pick type C2 protein to model membranes supports a role in lysosomal cholesterol transport. J. Biol. Chem. 281: 31594–31604

    CAS  PubMed  Google Scholar 

  • Chikh, K., Vey, S., Simonot, C., Vanier, M. T., Millat, G., 2004, Niemann-Pick type C disease: importance of N-glycosylation sites for function and cellular location of the NPC2 protein. Mol. Genet. Metab. 83: 220–230

    CAS  PubMed  Google Scholar 

  • Cruz, J. C., Chang, T. Y., 2000, Fate of endogenously synthesized cholesterol in Niemann-Pick type C1 cells. J. Biol. Chem. 275: 41309–41316

    CAS  PubMed  Google Scholar 

  • Davies, J. P., Chen, F. W., Ioannou, Y. A., 2000a, Transmembrane molecular pump activity of Niemann-Pick C1 protein. Science 290: 2295–2298

    CAS  PubMed  Google Scholar 

  • Davies, J. P., Ioannou, Y. A., 2000, Topological analysis of Niemann-Pick C1 protein reveals that the membrane orientation of the putative sterol-sensing domain is identical to those of 3-hydroxy-3-methylglutaryl-CoA reductase and sterol regulatory element binding protein cleavage-activating protein. J. Biol. Chem. 275: 24367–24374

    CAS  PubMed  Google Scholar 

  • Davies, J. P., Levy, B., Ioannou, Y. A., 2000b, Evidence for a Niemann-pick C (NPC) gene family: identification and characterization of NPC1L1. Genomics 65: 137–145

    CAS  PubMed  Google Scholar 

  • Dietschy, J. M., Turley, S. D., 2001, Cholesterol metabolism in the brain. Curr. Opin. Lipidol. 12: 105–112

    CAS  PubMed  Google Scholar 

  • Distl, R., Treiber-Held, S., Albert, F., Meske, V., Harzer, K., Ohm, T. G., 2003, Cholesterol storage and tau pathology in Niemann-Pick type C disease in the brain. J. Pathol. 200: 104–111

    CAS  PubMed  Google Scholar 

  • Fink, J. K., Filling-Katz, M. R., Sokol, J., Cogan, D. G., Pikus, A., Sonies, B., Soong, B., Pentchev, P. G., Comly, M. E., Brady, R. O., et al., 1989, Clinical spectrum of Niemann-Pick disease type C. Neurology 39: 1040–1049

    CAS  PubMed  Google Scholar 

  • Friedland, N., Liou, H. L., Lobel, P., Stock, A. M., 2003, Structure of a cholesterol-binding protein deficient in Niemann-Pick type C2 disease. Proc. Natl. Acad. Sci. USA 100: 2512–2517

    CAS  PubMed  Google Scholar 

  • German, D. C., Liang, C. L., Song, T., Yazdani, U., Xie, C., Dietschy, J. M., 2002, Neurodegeneration in the Niemann-Pick C mouse: glial involvement. Neuroscience 109: 437–450

    CAS  PubMed  Google Scholar 

  • German, D. C., Quintero, E. M., Liang, C., Xie, C., Dietschy, J. M., 2001, Degeneration of neurons and glia in the Niemann-Pick C mouse is unrelated to the low-density lipoprotein receptor. Neuroscience 105: 999–1005

    CAS  PubMed  Google Scholar 

  • Gofflot, F., Chartoire, N., Vasseur, L., Heikkinen, S., Dembele, D., Le Merrer, J., Auwerx, J., 2007, Systematic gene expression mapping clusters nuclear receptors according to their function in the brain. Cell 131: 405–418

    CAS  PubMed  Google Scholar 

  • Gondre-Lewis, M. C., McGlynn, R., Walkley, S. U., 2003, Cholesterol accumulation in NPC1-deficient neurons is ganglioside dependent. Curr. Biol. 13: 1324–1329

    CAS  PubMed  Google Scholar 

  • Gong, J. S., Kobayashi, M., Hayashi, H., Zou, K., Sawamura, N., Fujita, S. C., Yanagisawa, K., Michikawa, M., 2002, Apolipoprotein E (ApoE) isoform-dependent lipid release from astrocytes prepared from human ApoE3 and ApoE4 knock-in mice. J. Biol. Chem. 277: 29919–29926

    CAS  PubMed  Google Scholar 

  • Griffin, L. D., Gong, W., Verot, L., Mellon, S. H., 2004, Niemann-Pick type C disease involves disrupted neurosteroidogenesis and responds to allopregnanolone. Nat. Med. 10: 704–711

    CAS  PubMed  Google Scholar 

  • Hardy, J., Lewis, P., Revesz, T., Lees, A., Paisan-Ruiz, C., 2009, The genetics of Parkinson’s syndromes: a critical review. Curr. Opin. Genet. Dev. 19: 254–265

    CAS  PubMed  Google Scholar 

  • Henderson, L. P., Lin, L., Prasad, A., Paul, C. A., Chang, T. Y., Maue, R. A., 2000, Embryonic striatal neurons from Niemann-Pick type C mice exhibit defects in cholesterol metabolism and neurotrophin responsiveness. J. Biol. Chem. 275: 20179–20187

    CAS  PubMed  Google Scholar 

  • Higashi, Y., Murayama, S., Pentchev, P. G., Suzuki, K., 1993, Cerebellar degeneration in the Niemann-Pick type C mouse. Acta Neuropathol. 85: 175–184

    CAS  PubMed  Google Scholar 

  • Higgins, M. E., Davies, J. P., Chen, F. W., Ioannou, Y. A., 1999, Niemann-Pick C1 is a late endosome-resident protein that transiently associates with lysosomes and the trans-Golgi network. Mol. Genet. Metab. 68: 1–13

    CAS  PubMed  Google Scholar 

  • Infante, R. E., Abi-Mosleh, L., Radhakrishnan, A., Dale, J. D., Brown, M. S., Goldstein, J. L., 2008a, Purified NPC1 protein. I. Binding of cholesterol and oxysterols to a 1278-amino acid membrane protein. J. Biol. Chem. 283: 1052–1063

    CAS  PubMed  Google Scholar 

  • Infante, R. E., Radhakrishnan, A., Abi-Mosleh, L., Kinch, L. N., Wang, M. L., Grishin, N. V., Goldstein, J. L., Brown, M. S., 2008b, Purified NPC1 protein: II. Localization of sterol binding to a 240-amino acid soluble luminal loop. J. Biol. Chem. 283: 1064–1075

    CAS  PubMed  Google Scholar 

  • Infante, R. E., Wang, M. L., Radhakrishnan, A., Kwon, H. J., Brown, M. S., Goldstein, J. L., 2008c, NPC2 facilitates bidirectional transfer of cholesterol between NPC1 and lipid bilayers, a step in cholesterol egress from lysosomes. Proc. Natl. Acad. Sci. USA 105: 15287–15292

    CAS  PubMed  Google Scholar 

  • Ishibashi, S., Yamazaki, T., Okamoto, K., 2009, Association of autophagy with cholesterol-accumulated compartments in Niemann-Pick disease type C cells. J. Clin. Neurosci. 16: 954–959

    CAS  PubMed  Google Scholar 

  • Jin, L. W., Shie, F. S., Maezawa, I., Vincent, I., Bird, T., 2004, Intracellular accumulation of amyloidogenic fragments of amyloid-beta precursor protein in neurons with Niemann-Pick type C defects is associated with endosomal abnormalities. Am. J. Pathol. 164: 975–985

    CAS  PubMed  Google Scholar 

  • Jurevics, H. A., Kidwai, F. Z., Morell, P., 1997, Sources of cholesterol during development of the rat fetus and fetal organs. J. Lipid Res. 38: 723–733

    CAS  PubMed  Google Scholar 

  • Kabeya, Y., Mizushima, N., Ueno, T., Yamamoto, A., Kirisako, T., Noda, T., Kominami, E., Ohsumi, Y., Yoshimori, T., 2000, LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J. 19: 5720–5728

    CAS  PubMed  Google Scholar 

  • Karten, B., Hayashi, H., Francis, G. A., Campenot, R. B., Vance, D. E., Vance, J. E., 2005, Generation and function of astroglial lipoproteins from Niemann-Pick type C1-deficient mice. Biochem. J. 387: 779–788

    CAS  PubMed  Google Scholar 

  • Karten, B., Vance, D. E., Campenot, R. B., Vance, J. E., 2002, Cholesterol accumulates in cell bodies, but is decreased in distal axons, of Niemann-Pick C1-deficient neurons. J. Neurochem. 83: 1154–1163

    CAS  PubMed  Google Scholar 

  • Kirchhoff, C., Osterhoff, C., Young, L., 1996, Molecular cloning and characterization of HE1, a major secretory protein of the human epididymis. Biol. Reprod. 54: 847–856

    CAS  PubMed  Google Scholar 

  • Klionsky, D. J., Abeliovich, H., Agostinis, P., Agrawal., D. K., Aliev, G., Askew, D. S., Baba, M., Baehrecke, E. H., Bahr, B. A., Ballabio, A., Bamber, B. A., Bassham, D. C., Bergamini, E., Bi, X., Biard-Piechaczyk, M., Blum, J. S., Bredesen, D. E., Brodsky, J. L., Brumell, J. H., Brunk, U. T., Bursch, W., Camougrand, N., Cebollero, E., Cecconi, F., Chen, Y., Chin, L. S., Choi, A., Chu, C. T., Chung, J., Clarke, P. G., Clark, R. S., Clarke, S. G., Clave, C., Cleveland, J. L., Codogno, P., Colombo, M. I., Coto-Montes, A., Cregg, J. M., Cuervo, A. M., Debnath, J., Demarchi, F., Dennis, P. B., Dennis, P. A., Deretic, V., Devenish, R. J., Di Sano, F., Dice, J. F., Difiglia, M., Dinesh-Kumar, S., Distelhorst, C. W., Djavaheri-Mergny, M., Dorsey, F. C., Droge, W., Dron, M., Dunn, W. A., Jr., Duszenko, M., Eissa, N. T., Elazar, Z., Esclatine, A., Eskelinen, E. L., Fesus, L., Finley, K. D., Fuentes, J. M., Fueyo, J., Fujisaki, K., Galliot, B., Gao, F. B., Gewirtz, D. A., Gibson, S. B., Gohla, A., Goldberg, A. L., Gonzalez, R., Gonzalez-Estevez, C., Gorski, S., Gottlieb, R. A., Haussinger, D., He, Y. W., Heidenreich, K., Hill, J. A., Hoyer-Hansen, M., Hu, X., Huang, W. P., Iwasaki, A., Jaattela, M., Jackson, W. T., Jiang, X., Jin, S., Johansen, T., Jung, J. U., Kadowaki, M., Kang, C., Kelekar, A., Kessel, D. H., Kiel, J. A., Kim, H. P., Kimchi, A., Kinsella, T. J., Kiselyov, K., Kitamoto, K., Knecht, E., Komatsu, M., Kominami, E., Kondo, S., Kovacs, A. L., Kroemer, G., Kuan, C. Y., Kumar, R., Kundu, M., Landry, J., Laporte, M., Le, W., Lei, H. Y., Lenardo, M. J., Levine, B., Lieberman, A., Lim, K. L., Lin, F. C., Liou, W., Liu, L. F., Lopez-Berestein, G., Lopez-Otin, C., Lu, B., Macleod, K. F., Malorni, W., Martinet, W., Matsuoka, K., Mautner, J., Meijer, A. J., Melendez, A., Michels, P., Miotto, G., Mistiaen, W. P., Mizushima, N., Mograbi, B., Monastyrska, I., Moore, M. N., Moreira, P. I., Moriyasu, Y., Motyl, T., Munz, C., Murphy, L. O., Naqvi, N. I., Neufeld, T. P., Nishino, I., Nixon, R. A., Noda, T., Nurnberg, B., Ogawa, M., Oleinick, N. L., Olsen, L. J., Ozpolat, B., Paglin, S., Palmer, G. E., Papassideri, I., Parkes, M., Perlmutter, D. H., Perry, G., Piacentini, M., Pinkas-Kramarski, R., Prescott, M., Proikas-Cezanne, T., Raben, N., Rami, A., Reggiori, F., Rohrer, B., Rubinsztein, D. C., Ryan, K. M., Sadoshima, J., Sakagami, H., Sakai, Y., Sandri, M., Sasakawa, C., Sass, M., Schneider, C., Seglen, P. O., Seleverstov, O., Settleman, J., Shacka, J. J., Shapiro, I. M., Sibirny, A., Silva-Zacarin, E. C., Simon, H. U., Simone, C., Simonsen, A., Smith, M. A., Spanel-Borowski, K., Srinivas, V., Steeves, M., Stenmark, H., Stromhaug, P. E., Subauste, C. S., Sugimoto, S., Sulzer, D., Suzuki, T., Swanson, M. S., Tabas, I., Takeshita, F., Talbot, N. J., Talloczy, Z., Tanaka, K., Tanida, I., Taylor, G. S., Taylor, J. P., Terman, A., Tettamanti, G., Thompson, C. B., Thumm, M., Tolkovsky, A. M., Tooze, S. A., Truant, R., Tumanovska, L. V., Uchiyama, Y., Ueno, T., Uzcategui, N. L., van der Klei, I., Vaquero, E. C., Vellai, T., Vogel, M. W., Wang, H. G., Webster, P., Wiley, J. W., Xi, Z., Xiao, G., Yahalom, J., Yang, J. M., Yap, G., Yin, X. M., Yoshimori, T., Yu, L., Yue, Z., Yuzaki, M., Zabirnyk, O., Zheng, X., Zhu, X., Deter, R. L., 2008, Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes. Autophagy 4: 151–175

    CAS  PubMed  Google Scholar 

  • Klionsky, D. J., Emr, S. D., 2000, Autophagy as a regulated pathway of cellular degradation. Science 290: 1717–1721

    CAS  PubMed  Google Scholar 

  • Ko, D. C., Binkley, J., Sidow, A., Scott, M. P., 2003, The integrity of a cholesterol-binding pocket in Niemann-Pick C2 protein is necessary to control lysosome cholesterol levels. Proc. Natl. Acad. Sci. USA 100: 2518–2525

    CAS  PubMed  Google Scholar 

  • Ko, D. C., Milenkovic, L., Beier, S. M., Manuel, H., Buchanan, J., Scott, M. P., 2005, Cell-autonomous death of cerebellar purkinje neurons with autophagy in Niemann-Pick type C disease. PLoS Genet. 1: 81–95

    CAS  PubMed  Google Scholar 

  • Kobayashi, T., Beuchat, M. H., Lindsay, M., Frias, S., Palmiter, R. D., Sakuraba, H., Parton, R. G., Gruenberg, J., 1999, Late endosomal membranes rich in lysobisphosphatidic acid regulate cholesterol transport. Nat. Cell Biol. 1: 113–118

    CAS  PubMed  Google Scholar 

  • Koh, C. H., Peng, Z. F., Ou, K., Melendez, A., Manikandan, J., Qi, R. Z., Cheung, N. S., 2007, Neuronal apoptosis mediated by inhibition of intracellular cholesterol transport: microarray and proteomics analyses in cultured murine cortical neurons. J. Cell Physiol. 211: 63–87

    CAS  PubMed  Google Scholar 

  • Koh, C. H., Qi, R. Z., Qu, D., Melendez, A., Manikandan, J., Bay, B. H., Duan, W., Cheung, N. S., 2006, U18666A-mediated apoptosis in cultured murine cortical neurons: role of caspases, calpains and kinases. Cell Signal. 18: 1572–1583

    CAS  PubMed  Google Scholar 

  • Langmade, S. J., Gale, S. E., Frolov, A., Mohri, I., Suzuki, K., Mellon, S. H., Walkley, S. U., Covey, D. F., Schaffer, J. E., Ory, D. S., 2006, Pregnane X receptor (PXR) activation: a mechanism for neuroprotection in a mouse model of Niemann-Pick C disease. Proc. Natl. Acad. Sci. USA 103: 13807–13812

    CAS  PubMed  Google Scholar 

  • Li, H., Repa, J. J., Valasek, M. A., Beltroy, E. P., Turley, S. D., German, D. C., Dietschy, J. M., 2005, Molecular, anatomical., and biochemical events associated with neurodegeneration in mice with Niemann-Pick type C disease. J. Neuropathol. Exp. Neurol. 64: 323–333

    CAS  PubMed  Google Scholar 

  • Li, H., Turley, S. D., Liu, B., Repa, J. J., Dietschy, J. M., 2008, GM2/GD2 and GM3 gangliosides have no effect on cellular cholesterol pools or turnover in normal or NPC1 mice. J. Lipid Res. 49: 1816–1828

    CAS  PubMed  Google Scholar 

  • Liao, G., Cheung, S., Galeano, J., Ji, A. X., Qin, Q., Bi, X., 2009, Allopregnanolone treatment delays cholesterol accumulation and reduces autophagic/lysosomal dysfunction and inflammation in Npc1-/- mouse brain. Brain Res. 1270: 140–151

    CAS  PubMed  Google Scholar 

  • Liao, G., Yao, Y., Liu, J., Yu, Z., Cheung, S., Xie, A., Liang, X., Bi, X., 2007, Cholesterol accumulation is associated with lysosomal dysfunction and autophagic stress in Npc1 -/- mouse brain. Am. J. Pathol. 171: 962–975

    CAS  PubMed  Google Scholar 

  • Liscum, L., Munn, N. J., 1999, Intracellular cholesterol transport. Biochim. Biophys. Acta 1438: 19–37

    CAS  PubMed  Google Scholar 

  • Liu, B., Li, H., Repa, J. J., Turley, S. D., Dietschy, J. M., 2008, Genetic variations and treatments that affect the lifespan of the NPC1 mouse. J. Lipid Res. 49: 663–669

    CAS  PubMed  Google Scholar 

  • Lloyd-Evans, E., Morgan, A. J., He, X., Smith, D. A., Elliot-Smith, E., Sillence, D. J., Churchill, G. C., Schuchman, E. H., Galione, A., Platt, F. M., 2008, Niemann-Pick disease type C1 is a sphingosine storage disease that causes deregulation of lysosomal calcium. Nat. Med. 14: 1247–1255

    CAS  PubMed  Google Scholar 

  • Loftus, S. K., Erickson, R. P., Walkley, S. U., Bryant, M. A., Incao, A., Heidenreich, R. A., Pavan, W. J., 2002, Rescue of neurodegeneration in Niemann-Pick C mice by a prion-promoter-driven Npc1 cDNA transgene. Hum. Mol. Genet. 11: 3107–3114

    CAS  PubMed  Google Scholar 

  • Loftus, S. K., Morris, J. A., Carstea, E. D., Gu, J. Z., Cummings, C., Brown, A., Ellison, J., Ohno, K., Rosenfeld, M. A., Tagle, D. A., Pentchev, P. G., Pavan, W. J., 1997, Murine model of Niemann-Pick C disease: mutation in a cholesterol homeostasis gene. Science 277: 232–235

    CAS  PubMed  Google Scholar 

  • Love, S., Bridges, L. R., Case, C. P., 1995, Neurofibrillary tangles in Niemann-Pick disease type C. Brain 118 (Pt 1): 119–129

    PubMed  Google Scholar 

  • Lynch, G., Bi, X., 2003, Lysosomes and brain aging in mammals. Neurochem. Res. 28: 1725–1734

    CAS  PubMed  Google Scholar 

  • Malathi, K., Higaki, K., Tinkelenberg, A. H., Balderes, D. A., Almanzar-Paramio, D., Wilcox, L. J., Erdeniz, N., Redican, F., Padamsee, M., Liu, Y., Khan, S., Alcantara, F., Carstea, E. D., Morris, J. A., Sturley, S. L., 2004, 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

    CAS  PubMed  Google Scholar 

  • Millard, E. E., Gale, S. E., Dudley, N., Zhang, J., Schaffer, J. E., Ory, D. S., 2005, The sterol-sensing domain of the Niemann-Pick C1 (NPC1) protein regulates trafficking of low density lipoprotein cholesterol. J. Biol. Chem. 280: 28581–28590

    CAS  PubMed  Google Scholar 

  • Mutka, A. L., Lusa, S., Linder, M. D., Jokitalo, E., Kopra, O., Jauhiainen, M., Ikonen, E., 2004, Secretion of sterols and the NPC2 protein from primary astrocytes. J. Biol. Chem. 279: 48654–48662

    CAS  PubMed  Google Scholar 

  • Naureckiene, S., Sleat, D. E., Lackland, H., Fensom, A., Vanier, M. T., Wattiaux, R., Jadot, M., Lobel, P., 2000, Identification of HE1 as the second gene of Niemann-Pick C disease. Science 290: 2298–2301

    CAS  PubMed  Google Scholar 

  • Neufeld, E. B., Wastney, M., Patel, S., Suresh, S., Cooney, A. M., Dwyer, N. K., Roff, C. F., Ohno, K., Morris, J. A., Carstea, E. D., Incardona, J. P., Strauss, J. F., 3rd, Vanier, M. T., Patterson, M. C., Brady, R. O., Pentchev, P. G., Blanchette-Mackie, E. J., 1999, The Niemann-Pick C1 protein resides in a vesicular compartment linked to retrograde transport of multiple lysosomal cargo. J. Biol. Chem. 274: 9627–9635

    CAS  PubMed  Google Scholar 

  • Niemann, A. (1914) Ein unbekanntes Krankheitsbild. Jahrbuch der Kinderheikunde 1.

    Google Scholar 

  • Nixon, R. A., 2007, Autophagy, amyloidogenesis and Alzheimer disease. J. Cell Sci. 120: 4081–4091

    CAS  PubMed  Google Scholar 

  • Ohgami, N., Ko, D. C., Thomas, M., Scott, M. P., Chang, C. C., Chang, T. Y., 2004, Binding between the Niemann-Pick C1 protein and a photoactivatable cholesterol analog requires a functional sterol-sensing domain. Proc. Natl. Acad. Sci. USA 101: 12473–12478

    CAS  PubMed  Google Scholar 

  • Ohm, T. G., Treiber-Held, S., Distl, R., Glockner, F., Schonheit, B., Tamanai, M., Meske, V., 2003, Cholesterol and tau protein–findings in Alzheimer’s and Niemann Pick C’s disease. Pharmacopsychiatry 36 Suppl 2: S120–S126

    CAS  PubMed  Google Scholar 

  • Ohsaki, Y., Sugimoto, Y., Suzuki, M., Hosokawa, H., Yoshimori, T., Davies, J. P., Ioannou, Y. A., Vanier, M. T., Ohno, K., Ninomiya, H., 2006, Cholesterol depletion facilitates ubiquitylation of NPC1 and its association with SKD1/Vps4. J. Cell Sci. 119: 2643–2653

    CAS  PubMed  Google Scholar 

  • Okamura, N., Kiuchi, S., Tamba, M., Kashima, T., Hiramoto, S., Baba, T., Dacheux, F., Dacheux, J. L., Sugita, Y., Jin, Y. Z., 1999, A porcine homolog of the major secretory protein of human epididymis, HE1, specifically binds cholesterol. Biochim. Biophys. Acta 1438: 377–387

    CAS  PubMed  Google Scholar 

  • Ong, W. Y., Hu, C. Y., Patel, S. C., 2002, Apolipoprotein D in the Niemann-Pick type C disease mouse brain: an ultrastructural immunocytochemical analysis. J. Neurocytol. 31: 121–129

    CAS  PubMed  Google Scholar 

  • Pacheco, C. D., Kunkel, R., Lieberman, A. P., 2007, Autophagy in Niemann-Pick C disease is dependent upon Beclin-1 and responsive to lipid trafficking defects. Hum. Mol. Genet. 16: 1495–1503

    CAS  PubMed  Google Scholar 

  • Pan, T., Kondo, S., Le, W., Jankovic, J., 2008, The role of autophagy-lysosome pathway in neurodegeneration associated with Parkinson’s disease. Brain 131: 1969–1978

    PubMed  Google Scholar 

  • Patel, S. C., Asotra, K., Patel, Y. C., McConathy, W. J., Patel, R. C., Suresh, S., 1995, Astrocytes synthesize and secrete the lipophilic ligand carrier apolipoprotein D. Neuroreport 6: 653–657

    CAS  PubMed  Google Scholar 

  • Pentchev, P. G., Comly, M. E., Kruth, H. S., Vanier, M. T., Wenger, D. A., Patel, S., Brady, R. O., 1985, A defect in cholesterol esterification in Niemann-Pick disease (type C) patients. Proc. Natl. Acad. Sci. USA 82: 8247–8251

    CAS  PubMed  Google Scholar 

  • Pick, L., 1933, Niemann–Pick‘s disease and other forms of so called xanthomatosis. Am. J. Med. Sci. 185: 601–616

    Google Scholar 

  • Pitas, R. E., Boyles, J. K., Lee, S. H., Foss, D., Mahley, R. W., 1987, Astrocytes synthesize apolipoprotein E and metabolize apolipoprotein E-containing lipoproteins. Biochim. Biophys. Acta 917: 148–161

    CAS  PubMed  Google Scholar 

  • Prasad, A., Fischer, W. A., Maue, R. A., Henderson, L. P., 2000, Regional and developmental expression of the Npc1 mRNA in the mouse brain. J. Neurochem. 75: 1250–1257

    CAS  PubMed  Google Scholar 

  • Ravikumar, B., Vacher, C., Berger, Z., Davies, J. E., Luo, S., Oroz, L. G., Scaravilli, F., Easton, D. F., Duden, R., O’Kane, C. J., Rubinsztein, D. C., 2004, Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat. Genet. 36: 585–595

    CAS  PubMed  Google Scholar 

  • Reid, P. C., Lin, S., Vanier, M. T., Ohno-Iwashita, Y., Harwood, H. J., Jr., Hickey, W. F., Chang, C. C., Chang, T. Y., 2008, Partial blockage of sterol biosynthesis with a squalene synthase inhibitor in early postnatal Niemann-Pick type C npcnih null mice brains reduces neuronal cholesterol accumulation, abrogates astrogliosis, but may inhibit myelin maturation. J. Neurosci. Meth. 168: 15–25

    CAS  Google Scholar 

  • Reid, P. C., Sakashita, N., Sugii, S., Ohno-Iwashita, Y., Shimada, Y., Hickey, W. F., Chang, T. Y., 2004, A novel cholesterol stain reveals early neuronal cholesterol accumulation in the Niemann-Pick type C1 mouse brain. J. Lipid Res. 45: 582–591

    CAS  PubMed  Google Scholar 

  • Reid, P. C., Sugii, S., Chang, T. Y., 2003, Trafficking defects in endogenously synthesized cholesterol in fibroblasts, macrophages, hepatocytes, and glial cells from Niemann-Pick type C1 mice. J. Lipid Res. 44: 1010–1019

    CAS  PubMed  Google Scholar 

  • Repa, J. J., Li, H., Frank-Cannon, T. C., Valasek, M. A., Turley, S. D., Tansey, M. G., Dietschy, J. M., 2007, Liver X receptor activation enhances cholesterol loss from the brain, decreases neuroinflammation, and increases survival of the NPC1 mouse. J. Neurosci. 27: 14470–14480

    CAS  PubMed  Google Scholar 

  • Roff, C. F., Strauss, J. F., 3rd, Goldin, E., Jaffe, H., Patterson, M. C., Agritellis, G. C., Hibbs, A. M., Garfield, M., Brady, R. O., Pentchev, P. G., 1993, The murine Niemann-Pick type C lesion affects testosterone production. Endocrinology 133: 2913–2923

    CAS  PubMed  Google Scholar 

  • Runz, H., Dolle, D., Schlitter, A. M., Zschocke, J., 2008, NPC-db, a Niemann-Pick type C disease gene variation database. Hum. Mutat .29: 345–350

    CAS  PubMed  Google Scholar 

  • Saito, Y., Suzuki, K., Hulette, C. M., Murayama, S., 2004, Aberrant phosphorylation of alpha-synuclein in human Niemann-Pick type C1 disease. J. Neuropathol. Exp. Neurol. 63: 323–328

    CAS  PubMed  Google Scholar 

  • Saito, Y., Suzuki, K., Nanba, E., Yamamoto, T., Ohno, K., Murayama, S., 2002, Niemann-Pick type C disease: accelerated neurofibrillary tangle formation and amyloid beta deposition associated with apolipoprotein E epsilon 4 homozygosity. Ann. Neurol. 52: 351–355

    CAS  PubMed  Google Scholar 

  • Scott, C., Higgins, M. E., Davies, J. P., Ioannou, Y. A., 2004, Targeting of NPC1 to late endosomes involves multiple signals, including one residing within the putative sterol-sensing domain. J. Biol. Chem. 279: 48214–48223

    CAS  PubMed  Google Scholar 

  • Scott, C., Ioannou, Y. A., 2004, The NPC1 protein: structure implies function. Biochim. Biophys. Acta 1685: 8–13

    CAS  PubMed  Google Scholar 

  • Sleat, D. E., Wiseman, J. A., El-Banna, M., Price, S. M., Verot, L., Shen, M. M., Tint, G. S., Vanier, M. T., Walkley, S. U., Lobel, P., 2004, Genetic evidence for nonredundant functional cooperativity between NPC1 and NPC2 in lipid transport. Proc. Natl. Acad. Sci. USA 101: 5886–5891

    CAS  PubMed  Google Scholar 

  • Sokol, J., Blanchette-Mackie, J., Kruth, H. S., Dwyer, N. K., Amende, L. M., Butler, J. D., Robinson, E., Patel, S., Brady, R. O., Comly, M. E., et al., 1988, Type C Niemann-Pick disease. Lysosomal accumulation and defective intracellular mobilization of low density lipoprotein cholesterol. J. Biol. Chem. 263: 3411–3417

    CAS  PubMed  Google Scholar 

  • Suresh, S., Yan, Z., Patel, R. C., Patel, Y. C., Patel, S. C., 1998, Cellular cholesterol storage in the Niemann-Pick disease type C mouse is associated with increased expression and defective processing of apolipoprotein D. J. Neurochem. 70: 242–251

    CAS  PubMed  Google Scholar 

  • Suzuki, K., Parker, C. C., Pentchev, P. G., Katz, D., Ghetti, B., D’Agostino, A. N., Carstea, E. D., 1995, Neurofibrillary tangles in Niemann-Pick disease type C. Acta Neuropathol. 89: 227–238

    CAS  PubMed  Google Scholar 

  • Tanida, I., Minematsu-Ikeguchi, N., Ueno, T., Kominami, E., 2005, Lysosomal turnover, but not a cellular level, of endogenous LC3 is a marker for autophagy. Autophagy 1: 84–91

    CAS  PubMed  Google Scholar 

  • te Vruchte, D., Lloyd-Evans, E., Veldman, R. J., Neville, D. C., Dwek, R. A., Platt, F. M., van Blitterswijk, W. J., Sillence, D. J., 2004, Accumulation of glycosphingolipids in Niemann-Pick C disease disrupts endosomal transport. J. Biol. Chem. 279: 26167–26175

    Google Scholar 

  • Turley, S. D., Burns, D. K., Rosenfeld, C. R., Dietschy, J. M., 1996, Brain does not utilize low density lipoprotein-cholesterol during fetal and neonatal development in the sheep. J. Lipid Res. 37: 1953–1961

    CAS  PubMed  Google Scholar 

  • Urano, Y., Watanabe, H., Murphy, S. R., Shibuya, Y., Geng, Y., Peden, A. A., Chang, C. C., Chang, T. Y., 2008, Transport of LDL-derived cholesterol from the NPC1 compartment to the ER involves the trans-Golgi network and the SNARE protein complex. Proc. Natl. Acad. Sci. USA 105: 16513–16518

    CAS  PubMed  Google Scholar 

  • Vance, J. E., 2006, Lipid imbalance in the neurological disorder, Niemann-Pick C disease. FEBS Lett. 580: 5518–5524

    CAS  PubMed  Google Scholar 

  • Vanier, M. T., Millat, G., 2004, Structure and function of the NPC2 protein. Biochim. Biophys. Acta 1685: 14–21

    CAS  PubMed  Google Scholar 

  • Vanier, M. T., Wenger, D. A., Comly, M. E., Rousson, R., Brady, R. O., Pentchev, P. G., 1988, Niemann-Pick disease group C: clinical variability and diagnosis based on defective cholesterol esterification. A collaborative study on 70 patients. Clin. Genet. 33: 331–348

    CAS  PubMed  Google Scholar 

  • Walkley, S. U., Suzuki, K., 2004, Consequences of NPC1 and NPC2 loss of function in mammalian neurons. Biochim. Biophys. Acta 1685: 48–62

    CAS  PubMed  Google Scholar 

  • Watanabe, Y., Akaboshi, S., Ishida, G., Takeshima, T., Yano, T., Taniguchi, M., Ohno, K., Nakashima, K., 1998, Increased levels of GM2 ganglioside in fibroblasts from a patient with juvenile Niemann-Pick disease type C. Brain Dev. 20: 95–97

    CAS  PubMed  Google Scholar 

  • Weisgraber, K. H., Roses, A. D., Strittmatter, W. J., 1994, The role of apolipoprotein E in the nervous system. Curr. Opin. Lipidol. 5: 110–116

    CAS  PubMed  Google Scholar 

  • Willenborg, M., Schmidt, C. K., Braun, P., Landgrebe, J., von Figura, K., Saftig, P., Eskelinen, E. L., 2005, Mannose 6-phosphate receptors, Niemann-Pick C2 protein, and lysosomal cholesterol accumulation. J. Lipid Res. 46: 2559–2569

    CAS  PubMed  Google Scholar 

  • Wu, Y. P., Mizukami, H., Matsuda, J., Saito, Y., Proia, R. L., Suzuki, K., 2005, Apoptosis accompanied by up-regulation of TNF-alpha death pathway genes in the brain of Niemann-Pick type C disease. Mol. Genet. Metab. 84: 9–17

    CAS  PubMed  Google Scholar 

  • Xie, C., Burns, D. K., Turley, S. D., Dietschy, J. M., 2000, Cholesterol is sequestered in the brains of mice with Niemann-Pick type C disease but turnover is increased. J. Neuropathol. Exp. Neurol. 59: 1106–1117

    CAS  PubMed  Google Scholar 

  • Xie, C., Lund, E. G., Turley, S. D., Russell, D. W., Dietschy, J. M., 2003, Quantitation of two pathways for cholesterol excretion from the brain in normal mice and mice with neurodegeneration. J. Lipid Res. 44: 1780–1789

    CAS  PubMed  Google Scholar 

  • Xie, Z., Klionsky, D. J., 2007, Autophagosome formation: core machinery and adaptations. Nat. Cell Biol. 9: 1102–1109

    CAS  PubMed  Google Scholar 

  • Xu, S., Benoff, B., Liou, H. L., Lobel, P., Stock, A. M., 2007, Structural basis of sterol binding by NPC2, a lysosomal protein deficient in Niemann-Pick type C2 disease. J. Biol. Chem. 282: 23525–23531

    CAS  PubMed  Google Scholar 

  • Xu, Z., Farver, W., Kodukula, S., Storch, J., 2008, Regulation of sterol transport between membranes and NPC2. Biochemistry 47: 11134–11143

    CAS  PubMed  Google Scholar 

  • Zervas, M., Dobrenis, K., Walkley, S. U., 2001a, Neurons in Niemann-Pick disease type C accumulate gangliosides as well as unesterified cholesterol and undergo dendritic and axonal alterations. J. Neuropathol. Exp. Neurol. 60: 49–64

    CAS  PubMed  Google Scholar 

  • Zervas, M., Somers, K. L., Thrall, M. A., Walkley, S. U., 2001b, Critical role for glycosphingolipids in Niemann-Pick disease type C. Curr. Biol. 11: 1283–1287

    CAS  PubMed  Google Scholar 

  • Zhang, M., Strnatka, D., Donohue, C., Hallows, J. L., Vincent, I., Erickson, R. P., 2008, Astrocyte-only Npc1 reduces neuronal cholesterol and triples life span of Npc1(-/-) mice. J. Neurosci. Res. 86:2848–2456

    Google Scholar 

  • Zhang, M., Sun, M., Dwyer, N. K., Comly, M. E., Patel, S. C., Sundaram, R., Hanover, J. A., Blanchette-Mackie, E. J., 2003, Differential trafficking of the Niemann-Pick C1 and 2 proteins highlights distinct roles in late endocytic lipid trafficking. Acta Paediatr. Suppl. 92: 63–73

    CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by a grant from NINDS (NS048423 to XB) and by funds from Western University of Health Sciences (Pomona, CA) to X.B. Xiaoning Bi was also supported by funds from the Daljit and Elaine Sarkaria Chair.

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  1. Department of Basic Medical Sciences, COMP, Western University of Health Sciences, Pomona, CA, 91766, USA

    Xiaoning Bi & Guanghong Liao

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    J. Robin Harris

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Bi, X., Liao, G. (2010). Cholesterol in Niemann–Pick Type C disease. In: Harris, J. (eds) Cholesterol Binding and Cholesterol Transport Proteins:. Subcellular Biochemistry, vol 51. Springer, Dordrecht. https://doi.org/10.1007/978-90-481-8622-8_11

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