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Interference of CREB-dependent transcriptional activation by expanded polyglutamine stretches--augmentation of

M Shimohata1, T Shimohata, S Igarashi

  • 1Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan. m-shimohata@pop17.odn.ne.jp

Journal of Neurochemistry
|April 20, 2005
PubMed

Insights

Expanded polyglutamine proteins disrupt gene transcription by inhibiting cAMP-responsive element binding protein (CREB). Restoring CREB activity with cAMP or a histone deacetylase inhibitor reduces cell death, suggesting a therapeutic strategy for polyglutamine diseases.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Mutant proteins with expanded polyglutamine stretches are implicated in neurodegenerative diseases.
  • These proteins are hypothesized to cause transcriptional dysregulation through interactions with co-activators like TAFII130.

Purpose of the Study:

  • To investigate the transcriptional activation of c-Fos and its suppression by expanded polyglutamine stretches.
  • To explore potential therapeutic strategies targeting CREB-dependent transcriptional activation.

Main Methods:

  • Neuro2a cells expressing expanded polyglutamine were used.
  • Investigated the effects of cAMP, a histone deacetylase inhibitor (FR901228), and dominant-negative CREB vectors.
  • Assessed CREB phosphorylation, c-Fos expression, and nuclear fragmentation.

Main Results:

  • Expanded polyglutamine suppressed CREB phosphorylation and c-Fos induction in response to cAMP.
  • Increased cAMP concentration or FR901228 treatment rescued these suppressions and reduced cytotoxicity.
  • Dominant-negative CREB vectors diminished the protective effects of cAMP and FR901228.

Conclusions:

  • Interference with CREB-dependent transcriptional activation by expanded polyglutamine contributes to neurodegeneration.
  • Augmenting CREB activity is a promising therapeutic approach for polyglutamine diseases.

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