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http://dx.doi.org/10.14348/molcells.2014.2347

Inhibition of GM3 Synthase Attenuates Neuropathology of Niemann-Pick Disease Type C by Affecting Sphingolipid Metabolism  

Lee, Hyun (Stem Cell Neuroplasticity Research Group, Kyungpook National University)
Lee, Jong Kil (Stem Cell Neuroplasticity Research Group, Kyungpook National University)
Bae, Yong Chul (Department of Oral Anatomy and Neurobiology, Kyungpook National University)
Yang, Song Hyun (Institute of Metabolism, Green Cross Reference Laboratory)
Okino, Nozomu (Department of Bioscience and Biotechnology, Graduate School of Bioresource and Bioenvironmental Sciences, Kyushu University)
Schuchman, Edward H. (Department of Genetics and Genomic Sciences & Gene and Cell Therapy, Mount Sinai School of Medicine)
Yamashita, Tadashi (World Class University Program, Kyungpook National University)
Bae, Jae-Sung (Stem Cell Neuroplasticity Research Group, Kyungpook National University)
Jin, Hee Kyung (Stem Cell Neuroplasticity Research Group, Kyungpook National University)
Publication Information
Molecules and Cells / v.37, no.2, 2014 , pp. 161-171 More about this Journal
Abstract
In several lysosomal storage disorders, including Niemann-Pick disease Type C (NP-C), sphingolipids, including glycosphingolipids, particularly gangliosides, are the predominant storage materials in the brain, raising the possibility that accumulation of these lipids may be involved in the NP-C neurodegenerative process. However, correlation of these accumulations and NP-C neuropathology has not been fully characterized. Here we derived NP-C mice with complete and partial deletion of the Siat9 (encoding GM3 synthase) gene in order to investigate the role of ganglioside in NP-C pathogenesis. According to our results, NP-C mice with homozygotic deletion of GM3 synthase exhibited an enhanced neuropathological phenotype and died significantly earlier than NP-C mice. Notably, in contrast to complete depletion, NP-C mice with partial deletion of the GM3 synthase gene showed ameliorated NP-C neuropathology, including motor disability, demyelination, and abnormal accumulation of cholesterol and sphingolipids. These findings indicate the crucial role of GM3 synthesis in the NP-C phenotype and progression of CNS pathologic abnormality, suggesting that well-controlled inhibition of GM3 synthesis could be used as a therapeutic strategy.
Keywords
GM3; neuropathology; Niemann-pick type C disease; sphingolipids;
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1 Fishman, P.H., and Brady, R.O. (1976). Biosynthesis and function of gangliosides. Science 194, 906-915.   DOI
2 Ariga, T., Miyatake, T., and Yu, R.K. (2001). Recent studies on the roles of antiglycosphingolipids in the pathogenesis of neurological disorders. J. Neurosci. Res. 65, 363-370.   DOI   ScienceOn
3 Brunetti-Pierri, N., and Scaglia, F. (2008). GM1 gangliosidosis: review of clinical, molecular, and therapeutic aspects. Mol. Genet. Metab. 94, 391-396.   DOI   ScienceOn
4 Campbell, M.J., and Morrison, J.H. (1989). Monoclonal antibody to neurofilament protein (SMI-32) labels a subpopulation of pyramidal neurons in the human and monkey neocortex. J. Comp. Neurol. 282, 191-205.   DOI   ScienceOn
5 Di Rocco, M., Dardis, A., Madeo, A., Barone, R., and Fiumara, A. (2012). Early miglustat therapy in infantile Niemann-Pick disease type C. Pediatr. Neurol. 47, 40-43.   DOI   ScienceOn
6 Futerman, A.H., and van Meer, G. (2004). The cell biology of lysosomal storage disorders. Nat. Rev. Mol. Cell. Biol. 5, 554-565.20.   DOI   ScienceOn
7 German, D.C., Liang, C.L., Song, T., Yazdani, U., Xie, C., and Dietschy, J.M. (2002). Neurodegeneration in the Niemann-Pick C mouse: glial involvement. Neuroscience 109, 437-450.   DOI   ScienceOn
8 Gondre-Lewis, M.C., McGlynn, R., and Walkley, S.U. (2003). Cholesterol accumulation in NPC1-deficient neurons is ganglioside dependent. Curr. Biol. 13, 1324-1329.   DOI   ScienceOn
9 Hayashi, H., Kimura, N., Yamaguchi, H., Hasegawa, K., Yokoseki, T., Shibata, M., Yamamoto, N., Michikawa, M., Yoshikawa, Y., Terao, K., et al. (2004). A seed for Alzheimer amyloid in the brain. J. Neurosci. 24, 4894-4902.   DOI   ScienceOn
10 Lee, H., Lee, J.K., Min, W.K., Bae, J.H., He, X., Schuchman, E.H., Bae, J.S., and Jin, H.K. (2010). Bone marrow-derived mesenchymal stem cells prevent the loss of Niemann-Pick type C mouse Purkinje neurons by correcting sphingolipid metabolism and increasing sphingosine-1-phosphate. Stem Cells 28, 821-831.   DOI   ScienceOn
11 He, X., Dagan, A., Gatt, S., and Schuchman, E.H. (2005). 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.   DOI   ScienceOn
12 Karimzadeh, P., Tonekaboni, S.H., Ashrafi, M.R., Shafeghati, Y., Rezayi, A., Salehpour, S., Ghofrani, M., Taghdiri, M.M., Rahmanifar, A., Zaman, T., et al. (2013). Effects of miglustat on stabilization of neurological disorder in niemann-pick disease type C: iranian pediatric case series. J. Child Neuol. 28, 1599-1606.
13 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., et al. (1997). Murine model of Niemann-Pick C disease: mutation in a cholesterol homeostasis gene. Science 277, 232-235.   DOI   ScienceOn
14 Lachmann, R.H., te Vruchte, D., Lloyd-Evans, E., Reinkensmeier, G., Sillence, D.J., Fernandez-Guillen, L., Dwek, R.A., Butters, T.D., Cox, T.M., and Platt, F.M. (2004). Treatment with miglustat reverses the lipid-trafficking defect in Niemann-Pick disease type C. Neurobiol. Dis. 16, 654-658.   DOI   ScienceOn
15 Lehmann, F., Wegerhoff, R., Rosenberg, A., Schauer, R., and Kohla, G. (2003). Early variations of the disialoganglioside GD3 in chicken embryonic brain support its role in cell migration. Biochimie 85, 449-454.   DOI   ScienceOn
16 Liu, B., Turley, S.D., Burns, D.K., Miller, A.M., Repa, J.J., and Dietschy, J.M. (2009). Reversal of defective lysosomal transport in NPC disease ameliorates liver dysfunction and neurodegeneration in the npc1-/- mouse. Proc. Natl. Acad. Sci. USA 106, 2377-2382.   DOI   ScienceOn
17 Paciorkowski, A.R., Westwell, M., Ounpuu, S., Bell, K., Kagan, J., Mazzarella, C., and Greenstein, R.M. (2008). Motion analysis of a child with Niemann-Pick disease type C treated with miglustat. Movement Disord. 23, 124-128.   DOI   ScienceOn
18 Ridgway, N.D. (2000). Interactions between metabolism and intracellular distribution of cholesterol and sphingomyelin. Biochim. Biophys. Acta 1484, 129-141.   DOI   ScienceOn
19 Rosenbaum, A.I., and Maxfield, F.R. (2011). Niemann-Pick type C disease: molecular mechanisms and potential therapeutic approaches. J. Neurochem. 116, 789-795.   DOI   ScienceOn
20 Saadat, L., Dupree, J.L., Kilkus, J., Han. X., Traka, M., Proia, R.L., Dawson, G., and Popko, B. (2010). Absence of oligodendroglial glucosylceramide synthesis does not result in CNS myelin abnormalities or alter the dysmyelinating phenotype of CGT-deficient mice. Glia 58, 391-398.   DOI   ScienceOn
21 Shevchuk, N.A., Hathout, Y., Epifano, O., Su, Y., Liu, Y., Sutherland, M., and Ladisch, S. (2007). Alteration of ganglioside synthesis by GM3 synthase knockout in murine embryonic fibroblasts. Biochim. Biophys. Acta 1771, 1226-1234.   DOI   ScienceOn
22 Simons, K., and Ikonen, E. (1997). Functional rafts in cell membranes. Nature 387, 569-572.   DOI   ScienceOn
23 Skorpen, J., Helland, I.B., and Tennoe, B. (2012). Use of miglustat in a child with late-infantile-onset Niemann-Pick disease type C and frequent seizures: a case report. J. Med. Case Rep. 6, 383.   DOI
24 Sonnino, S., Mauri, L., Chigorno, V., Mauri, L., Chigorno, V., and Prinetti, A. (2007). Gangliosides as components of lipid membrane domains. Glycobiology 17, 1R-13R.   DOI   ScienceOn
25 Vanier, M.T. (2010). Niemann-Pick disease type C. Orphanet. J. Rare. Dis. 5, 16.   DOI   ScienceOn
26 Takikita, S., Fukuda, T., Mohri, I., Yagi, T., and Suzuki, K. (2004). Perturbed myelination process of premyelinating oligodendrocyte in Niemann-Pick type C mouse. J. Neuropath. Exp. Neur. 63, 660-673.   DOI
27 Tamura, H., Takahashi, T., Ban, N., Torisu, H., Ninomiya, H., Takada, G., and Inagaki, N. (2006). Niemann-Pick type C disease: novel NPC1 mutations and characterization of the concomitant acid sphingomyelinase deficiency. Mol. Genet. Metab. 87, 113-121.   DOI   ScienceOn
28 Walkley, S.U., Zervas, M., and Wiseman, S. (2000). Gangliosides as modulators of dendritogenesis in normal and storage diseaseaffected pyramidal neurons. Cereb. Cortex 10, 1028-1037.   DOI   ScienceOn
29 Vanier, M.T., Duthel, S., Rodriguez-Lafrasse, C., Pentchev, P., and Carstea, E.D. (1996). Genetic heterogeneity in Niemann-Pick C disease: a study using somatic cell hybridization and linkage analysis. Am. J. Hum. Genet. 58, 118-125.
30 Walkley, S.U., Siegel, D.A., Dobrenis, K., and Zervas, M. (1998). GM2 ganglioside as a regulator of pyramidal neuron dendritogenesis. Ann. N.Y. Acad. Sci. 845, 188-199.   DOI
31 Xu, Y.H., Barnes, S., Sun, Y., and Grabowski, G.A. (2010). Multisystem disorders of glycosphingolipid and ganglioside metabolism. J. Lipid Res. 51, 1643-1675.   DOI   ScienceOn
32 Yu, R.K., Nakatani, Y., and Yanagisawa, M. (2009). The role of glycosphingolipid metabolism in the developing brain. J. Lipid Res. 50 Suppl, S440-445.   DOI
33 Yang, T., Knowles, J.K., Lu, Q., Zhang, H., Arancio, O., Moore, L.A., Chang, T., Wang, Q., Andreasson, K., Rajadas, J., et al. (2008). Small molecule, non-peptide p75 ligands inhibit Abeta-induced neurodegeneration and synaptic impairment. PLoS One 3, e3604.   DOI   ScienceOn
34 Yamashita, T., Hashiramoto, A., Haluzik, M., Mizukami, H., Beck, S., Norton, A., Kono, M., Tsuji, S., Daniotti, J.L., Werth, N., et al. (2003). Enhanced insulin sensitivity in mice lacking ganglioside GM3. Proc. Natl. Acad. Sci. USA 100, 3445-3449.   DOI   ScienceOn
35 Yoshikawa, M., Go, S., Takasaki, K., Kakazu, Y., Ohashi, M., Nagafuku, M., Kabayama, K., Sekimoto, J., Suzuki, S., Takaiwa, K., et al. (2009). Mice lacking ganglioside GM3 synthase exhibit complete hearing loss due to selective degeneration of the organ of Corti. Proc. Natl. Acad. Sci. USA 106, 9483-9488.   DOI   ScienceOn
36 Runz, H., Dolle, D., Schlitter, A.M., and Zschocke, J. (2008). NPCdb, a Niemann-Pick type C disease gene variation database. Hum. Mutat. 29, 345-350.   DOI   ScienceOn
37 Stein, V.M., Crooks, A., Ding, W., Prociuk, M., O'Donnell, P., Bryan, C., Sikora, T., Dingemanse, J., Vanier, M.T., Walkley, S.U., et al. (2012). Miglustat improves purkinje cell survival and alters microglial phenotype in feline Niemann-Pick disease type C. J. Neuropathol. Exp. Neurol. 71, 434-448.   DOI
38 Chen, Y., Balasubramaniyan, V., Peng, J., Hurlock, E.C., Tallquist, M., Li, J., and Lu, Q.R. (2007). Isolation and culture of rat and mouse oligodendrocyte precursor cells. Nat. Protoc. 2, 1044-1051.   DOI   ScienceOn
39 Zervas, M., Dobrenis, K., and 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. Neuropath. Exp. Neur. 60, 49-64.   DOI
40 Zervas, M., Somers, K.L., Thrall, M.A., and Walkley, S.U. (2001b). Critical role for glycosphingolipids in Niemann-Pick disease type C. Curr. Biol. 11, 1283-1287.   DOI   ScienceOn