Ganglioside GM1 induces phosphorylation of mutant huntingtin and restores normal motor behavior in Huntington disease mice

Proc Natl Acad Sci U S A. 2012 Feb 28;109(9):3528-33. doi: 10.1073/pnas.1114502109. Epub 2012 Feb 13.


Huntington disease (HD) is a progressive neurodegenerative monogenic disorder caused by expansion of a polyglutamine stretch in the huntingtin (Htt) protein. Mutant huntingtin triggers neural dysfunction and death, mainly in the corpus striatum and cerebral cortex, resulting in pathognomonic motor symptoms, as well as cognitive and psychiatric decline. Currently, there is no effective treatment for HD. We report that intraventricular infusion of ganglioside GM1 induces phosphorylation of mutant huntingtin at specific serine amino acid residues that attenuate huntingtin toxicity, and restores normal motor function in already symptomatic HD mice. Thus, our studies have identified a potential therapy for HD that targets a posttranslational modification of mutant huntingtin with critical effects on disease pathogenesis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Video-Audio Media

MeSH terms

  • Animals
  • Codon / drug effects
  • Corpus Striatum / metabolism
  • Dimerization
  • Disease Models, Animal
  • Dopamine and cAMP-Regulated Phosphoprotein 32 / biosynthesis
  • Dopamine and cAMP-Regulated Phosphoprotein 32 / genetics
  • Drug Evaluation, Preclinical
  • G(M1) Ganglioside / administration & dosage
  • G(M1) Ganglioside / therapeutic use*
  • Huntingtin Protein
  • Infusion Pumps, Implantable
  • Infusions, Parenteral
  • Mice
  • Mice, Neurologic Mutants
  • Motor Activity / drug effects*
  • Nerve Tissue Proteins / biosynthesis
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Neurons / metabolism
  • Nuclear Proteins / metabolism*
  • Phosphorylation / drug effects
  • Phosphoserine / analysis
  • Protein Processing, Post-Translational / drug effects*
  • Psychomotor Performance / drug effects


  • Codon
  • Dopamine and cAMP-Regulated Phosphoprotein 32
  • Htt protein, mouse
  • Huntingtin Protein
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Ppp1r1b protein, mouse
  • Phosphoserine
  • G(M1) Ganglioside