p53 mediates cellular dysfunction and behavioral abnormalities in Huntington's disease

Neuron. 2005 Jul 7;47(1):29-41. doi: 10.1016/j.neuron.2005.06.005.


We present evidence for a specific role of p53 in the mitochondria-associated cellular dysfunction and behavioral abnormalities of Huntington's disease (HD). Mutant huntingtin (mHtt) with expanded polyglutamine (polyQ) binds to p53 and upregulates levels of nuclear p53 as well as p53 transcriptional activity in neuronal cultures. The augmentation is specific, as it occurs with mHtt but not mutant ataxin-1 with expanded polyQ. p53 levels are also increased in the brains of mHtt transgenic (mHtt-Tg) mice and HD patients. Perturbation of p53 by pifithrin-alpha, RNA interference, or genetic deletion prevents mitochondrial membrane depolarization and cytotoxicity in HD cells, as well as the decreased respiratory complex IV activity of mHtt-Tg mice. Genetic deletion of p53 suppresses neurodegeneration in mHtt-Tg flies and neurobehavioral abnormalities of mHtt-Tg mice. Our findings suggest that p53 links nuclear and mitochondrial pathologies characteristic of HD.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Behavior / physiology*
  • Behavior, Animal / physiology
  • Blotting, Northern
  • Cell Survival / physiology
  • Densitometry
  • Drosophila
  • Electron Transport / genetics
  • Electron Transport / physiology
  • Escape Reaction / physiology
  • Gene Deletion
  • Genes, Reporter / genetics
  • Humans
  • Huntingtin Protein
  • Huntington Disease / pathology*
  • Huntington Disease / psychology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mitochondria / physiology
  • Nerve Tissue Proteins / physiology*
  • Nerve Tissue Proteins / toxicity
  • Neurons / pathology*
  • Nuclear Proteins / physiology*
  • Nuclear Proteins / toxicity
  • Plasmids / genetics
  • Retinal Degeneration / genetics
  • Retinal Degeneration / pathology
  • Transcription, Genetic / physiology
  • Tumor Suppressor Protein p53 / physiology*


  • HTT protein, human
  • Htt protein, mouse
  • Huntingtin Protein
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Tumor Suppressor Protein p53