IRS2 increases mitochondrial dysfunction and oxidative stress in a mouse model of Huntington disease

J Clin Invest. 2011 Oct;121(10):4070-81. doi: 10.1172/JCI46305. Epub 2011 Sep 19.


Aging is a major risk factor for the progression of neurodegenerative diseases, including Huntington disease (HD). Reduced neuronal IGF1 or Irs2 signaling have been shown to extend life span in mice. To determine whether Irs2 signaling modulates neurodegeneration in HD, we genetically modulated Irs2 concentrations in the R6/2 mouse model of HD. Increasing Irs2 levels in the brains of R6/2 mice significantly reduced life span and increased neuronal oxidative stress and mitochondrial dysfunction. In contrast, reducing Irs2 levels throughout the body (except in β cells, where Irs2 expression is needed to prevent diabetes onset; R6/2•Irs2+/-•Irs2βtg mice) improved motor performance and extended life span. The slower progression of HD-like symptoms was associated with increased nuclear localization of the transcription factor FoxO1 and increased expression of FoxO1-dependent genes that promote autophagy, mitochondrial function, and resistance to oxidative stress. Mitochondrial function improved and the number of autophagosomes increased in R6/2•Irs2+/-•Irs2βtg mice, whereas aggregate formation and oxidative stress decreased. Thus, our study suggests that Irs2 signaling can modulate HD progression. Since we found the expression of Irs2 to be normal in grade II HD patients, our results suggest that decreasing IRS2 signaling could be part of a therapeutic approach to slow the progression of HD.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / genetics
  • Aging / physiology
  • Animals
  • Brain / pathology
  • Brain / physiopathology
  • Disease Models, Animal
  • Disease Progression
  • Female
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors / metabolism
  • Gene Expression
  • Humans
  • Huntington Disease / genetics
  • Huntington Disease / pathology
  • Huntington Disease / physiopathology*
  • Insulin Receptor Substrate Proteins / deficiency
  • Insulin Receptor Substrate Proteins / genetics
  • Insulin Receptor Substrate Proteins / physiology*
  • Longevity / genetics
  • Longevity / physiology
  • Male
  • Mice
  • Mice, Knockout
  • Mice, Mutant Strains
  • Mice, Transgenic
  • Mitochondria / physiology*
  • Oxidative Stress
  • Signal Transduction


  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Foxo1 protein, mouse
  • Insulin Receptor Substrate Proteins
  • Irs2 protein, mouse