Oxidative stress promotes mutant huntingtin aggregation and mutant huntingtin-dependent cell death by mimicking proteasomal malfunction

Biochem Biophys Res Commun. 2006 Mar 31;342(1):184-90. doi: 10.1016/j.bbrc.2006.01.136. Epub 2006 Feb 3.


Huntington's disease (HD) is a familial neurodegenerative disorder caused by an abnormal expansion of CAG repeats in the coding region of huntingtin gene. A major hallmark of HD is the proteolytic production of N-terminal fragments of huntingtin containing polyglutamine repeats that form ubiquitinated aggregates in the nucleus and cytoplasm of the affected neurons. However, the mechanism by which the mutant huntingtin causes neurodegeneration is not well understood. Here, we found that oxidative stimuli enhance the polyglutamine-expanded truncated N-terminal huntingtin (mutant huntingtin) aggregation and mutant huntingtin-induced cell death. Oxidative stimuli also lead to rapid proteasomal dysfunction in the mutant huntingtin expressing cells as compared to normal glutamine repeat expressing cells. Overexpression of Cu/Zn superoxide dismutase (SOD1), Hsp40 or Hsp70 reverses the oxidative stress-induced proteasomal malfunction, mutant huntingtin aggregation, and death of the mutant huntingtin expressing cells. Finally, we show the higher levels of expression of SOD1 and DJ-1 in the mutant huntingtin expressing cells. Our result suggests that oxidative stress-induced proteasomal malfunction might be linked with mutant huntingtin-induced cell death.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Death / drug effects
  • Cell Line
  • Gene Expression
  • HSP40 Heat-Shock Proteins / genetics
  • HSP40 Heat-Shock Proteins / metabolism
  • HSP70 Heat-Shock Proteins / genetics
  • HSP70 Heat-Shock Proteins / metabolism
  • Huntington Disease / genetics*
  • Huntington Disease / pathology
  • Mutation / genetics
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism*
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism*
  • Oncogene Proteins / metabolism
  • Oxidation-Reduction
  • Oxidative Stress*
  • Peptides / metabolism
  • Proteasome Endopeptidase Complex / metabolism*
  • Proteasome Inhibitors
  • Protein Binding
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase / metabolism
  • Superoxide Dismutase-1
  • Time Factors
  • Ubiquitin / metabolism


  • HSP40 Heat-Shock Proteins
  • HSP70 Heat-Shock Proteins
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Oncogene Proteins
  • Peptides
  • Proteasome Inhibitors
  • Ubiquitin
  • polyglutamine
  • Superoxide Dismutase
  • Superoxide Dismutase-1
  • Proteasome Endopeptidase Complex