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Bax-inhibiting peptide protects cells from polyglutamine toxicity caused by Ku70 acetylation

Y Li1, T Yokota, V Gama

  • 1Department of Neurology and Neurological Science, Tokyo Medical and Dental University, Tokyo, Japan.

Cell Death and Differentiation
|September 22, 2007
PubMed

Insights

Expanded polyglutamine (polyQ) tracts in Machado-Joseph disease stimulate Ku70 acetylation, promoting cell death. Bax-inhibiting peptides and SIRT1 activation offer potential therapeutic strategies for polyQ diseases.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Polyglutamine (polyQ) diseases result from toxic gain-of-function mutations in specific genes.
  • Machado-Joseph disease (MJD) is a polyQ disease caused by expanded polyQ tracts in the ataxin-3 gene.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying cell death in MJD.
  • To identify potential therapeutic targets for polyQ diseases.

Main Methods:

  • Utilized cell models expressing expanded polyQ ataxin-3 (Q79C).
  • Assessed the role of Ku70 acetylation and Bax protein.
  • Investigated the effects of Ku70-derived Bax-inhibiting peptides (BIPs).
  • Examined the impact of SIRT1 deacetylase and its agonist resveratrol.

Main Results:

  • Expanded polyQ (Q79C) stimulates Ku70 acetylation, leading to Bax dissociation and activation.
  • Q79C-induced cell death was significantly reduced by Ku70 or BIPs.
  • SIRT1 expression and resveratrol treatment decreased Q79C toxicity.
  • Mimicking Ku70 acetylation abrogated its protective effect against Q79C toxicity.

Conclusions:

  • Ku70 acetylation and Bax activation are critical mediators of Q79C-induced cell death.
  • Bax-inhibiting peptides represent a promising therapeutic avenue for polyQ diseases.
  • Targeting SIRT1 may offer a strategy to mitigate polyQ disease progression.

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