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Mutant huntingtin represses CBP, but not p300, by binding and protein degradation

Shu-Yan Cong1, Barry A Pepers, Bernd O Evert

  • 1CBG-Center of Human and Clinical Genetics, Leiden University Medical Center, The Netherlands, and Department of Neurology, The second affiliated hospital of China Medical University, Shenyang, China.

Molecular and Cellular Neurosciences
|February 4, 2006
PubMed

Insights

Mutant huntingtin selectively represses CBP activity and reduces its levels, impacting transcription in neurodegenerative diseases. This specific effect on CBP, unlike p300, offers insights into Huntington's disease pathogenesis.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Huntington's disease (HD) serves as a model for protein aggregation disorders.
  • Transcription factor sequestration in aggregates is implicated in HD pathogenesis.

Purpose of the Study:

  • To investigate the impact of mutant huntingtin on CBP/p300 transcriptional coactivators.
  • To elucidate the mechanisms underlying CBP/p300 dysfunction in early and late stages of HD.

Main Methods:

  • Assessing CBP/p300 transcriptional and histone acetyltransferase activity in the presence of mutant huntingtin.
  • Quantifying CBP and p300 protein levels and their degradation pathways.
  • Comparing the effects of mutant huntingtin on CBP/p300 with other neurodegenerative conditions like spinocerebellar ataxia 3.

Main Results:

  • Soluble mutant huntingtin represses CBP transcriptional activity early on.
  • Mutant huntingtin binds CBP more strongly than wild-type huntingtin.
  • CBP protein levels decrease over time via proteasomal degradation, while p300 remains unaffected.
  • This selective CBP degradation is specific to HD and not observed in spinocerebellar ataxia 3.

Conclusions:

  • Mutant huntingtin selectively targets CBP through multiple mechanisms, affecting its activity and stability.
  • The differential impact on CBP versus p300 contributes to altered chromatin structure and transcription in HD.
  • Understanding these specific molecular events provides insights into HD neurodegeneration and potential therapeutic targets.

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