Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
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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)
  • Received : 2013.11.21
  • Accepted : 2013.12.18
  • Published : 2014.02.28
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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

References

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