AMPK-α1 functions downstream of oxidative stress to mediate neuronal atrophy in Huntington's disease

Biochim Biophys Acta. 2014 Sep;1842(9):1668-80. doi: 10.1016/j.bbadis.2014.06.012. Epub 2014 Jun 16.


Huntington's disease (HD) is an autosomal dominant neurological disorder that is induced by a CAG trinucleotide expansion in exon 1 of the Huntingtin (HTT) gene. We previously reported that the abnormal activation of an important energy sensor, AMP-activated protein kinase α1 (AMPK-α1), occurs in the brains of mice and patients with HD, which suggests that this abnormal activation may contribute to neuronal degeneration in HD. In the present study, we demonstrated that the elevated oxidative stress that was evoked by a polyQ-expanded mutant HTT (mHTT) caused the abnormal activation of AMPK-α1 and, subsequently, resulted in neurotoxicity in a striatal progenitor cell line (STHdh(Q109)) and in the striatum of a transgenic mouse model of HD (R6/2). The systematic administration of an antioxidant (N-acetyl-cysteine, NAC) to R6/2 mice suppressed the activation of AMPK-α1, reduced neuronal toxicity, which was assessed by the activation of caspases, increased neuronal density, ameliorated ventricle enlargement, and improved motor dysfunction. This beneficial effect of NAC in vivo appears to be direct because NAC also reduced the activation of AMPK-α1 and the death of STHdh(Q109) cells upon elevated oxidative stress. Moreover, the activation of AMPK enhanced the level of oxidative stress in STHdh(Q109) cells, in primary neurons of R6/2 mice, and in the striatum of two different HD mouse models (R6/2 and Hdh(150Q/+)), whereas the inhibition of AMPK reduced the level of oxidative stress. Collectively, our findings suggest that positive feedback regulation between the elevated oxidative stress and the activation of AMPK-α1 contributes to the progression of HD.

Keywords: AMP-activated protein kinase (AMPK); Huntington's disease (HD); N-acetyl-l-cysteine (NAC); Reactive oxygen species (ROS).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Animals
  • Apoptosis
  • Atrophy / metabolism
  • Atrophy / pathology*
  • Blotting, Western
  • Cell Proliferation
  • Cells, Cultured
  • Corpus Striatum / metabolism
  • Corpus Striatum / pathology*
  • Disease Models, Animal*
  • Humans
  • Huntingtin Protein
  • Huntington Disease / metabolism
  • Huntington Disease / pathology*
  • Immunoenzyme Techniques
  • Mice
  • Mice, Transgenic
  • Nerve Degeneration
  • Nerve Tissue Proteins / physiology*
  • Neurons / metabolism
  • Neurons / pathology*
  • Oxidative Stress*


  • HTT protein, human
  • Huntingtin Protein
  • Nerve Tissue Proteins
  • AMPK alpha1 subunit, mouse
  • AMP-Activated Protein Kinases