Impaired ganglioside metabolism in Huntington's disease and neuroprotective role of GM1

J Neurosci. 2010 Mar 17;30(11):4072-80. doi: 10.1523/JNEUROSCI.6348-09.2010.


Huntington's disease (HD) is a neurodegenerative disorder caused by the expansion of a polyglutamine stretch in the protein huntingtin (Htt). HD neurons are dysfunctional at multiple levels and have increased susceptibility to stress and apoptotic stimuli. We have discovered that synthesis of the ganglioside GM1 is reduced in fibroblasts from HD patients and in cell and animal models of HD, and that decreased GM1 levels contribute to heighten HD cell susceptibility to apoptosis. The apoptotic susceptibility is recapitulated through inhibition of ganglioside synthesis in wild-type striatal cells, suggesting that decreased GM1 levels might be one of the key events leading to HD pathogenesis and progression. Administration of GM1 restores ganglioside levels in HD cells and promotes activation of AKT and phosphorylation of mutant Htt, leading to decreased mutant Htt toxicity and increased survival of HD cells. Our data identify GM1 as a potential treatment for HD.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / metabolism*
  • Brain / pathology
  • Cell Line, Transformed
  • Cells, Cultured
  • Female
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • G(M1) Ganglioside / antagonists & inhibitors
  • G(M1) Ganglioside / genetics
  • G(M1) Ganglioside / pharmacology
  • G(M1) Ganglioside / physiology*
  • Gene Knock-In Techniques
  • Humans
  • Huntingtin Protein
  • Huntington Disease / genetics*
  • Huntington Disease / metabolism*
  • Male
  • Mice
  • Mice, Transgenic
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Neuroprotective Agents* / antagonists & inhibitors
  • Neuroprotective Agents* / metabolism
  • Neuroprotective Agents* / pharmacology
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Peptides / genetics
  • Rats


  • Htt protein, mouse
  • Huntingtin Protein
  • Nerve Tissue Proteins
  • Neuroprotective Agents
  • Nuclear Proteins
  • Peptides
  • polyglutamine
  • G(M1) Ganglioside