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

Mol Cells. 2014 Feb;37(2):161-71. doi: 10.14348/molcells.2014.2347. Epub 2014 Feb 19.


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, NPC 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Cerebellum / pathology
  • Cerebrum / pathology
  • Disease Models, Animal
  • G(M3) Ganglioside / metabolism*
  • Gene Deletion
  • Humans
  • Mice, Inbred BALB C
  • Mice, Transgenic
  • Niemann-Pick Disease, Type C / enzymology
  • Niemann-Pick Disease, Type C / pathology*
  • Sialyltransferases / genetics*
  • Sialyltransferases / metabolism*


  • G(M3) Ganglioside
  • Sialyltransferases
  • haematoside synthetase