Inhibition of GM3 synthase attenuates neuropathology of Niemann-Pick disease type C by affecting sphingolipid metabolism

Hyun Lee, Jong Kil Lee, Yong Chul Bae, Song Hyun Yang, Nozomu Okino, Edward H. Schuchman, Tadashi Yamashita, Jae Sung Bae, Hee Kyung Jin

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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.

Original languageEnglish
Pages (from-to)161-171
Number of pages11
JournalMolecules and cells
Issue number2
Publication statusPublished - Feb 2014


All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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