Jul 6, 2005

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

Neuron
Byoung-Il BaeAkira Sawa

Abstract

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.

  • References41
  • Citations232

Citations

Mentioned in this Paper

Examination of Reflexes
Photoreceptors
Embryo
Pathogenic Aspects
Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone
Cytochrome C Oxidase
Calcium [EPC]
Behavior, Animal
Tumor Suppressor Genes
MDM2 protein, human

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