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Fractionation for Resolution of Soluble and Insoluble Huntingtin Species
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Published on: February 27, 2018

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, Leiden, The Netherlands.

Molecular and Cellular Neurosciences
|July 5, 2005
PubMed

Insights

Mutant huntingtin selectively degrades CBP, a key protein, impacting transcription and contributing to neurodegeneration in Huntington's disease models. This selective protein loss differs from other neurodegenerative conditions.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Huntington's disease (HD) serves as a model for protein aggregation-related neurodegenerative disorders.
  • Transcription factor sequestration in aggregates is a proposed pathogenic mechanism in HD.

Purpose of the Study:

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

Main Methods:

  • Assessing transcriptional and histone acetyltransferase activity of CBP/p300.
  • Analyzing binding affinity of mutant huntingtin to CBP.
  • Investigating CBP protein degradation pathways.
  • Comparing CBP/p300 regulation in HD models versus spinocerebellar ataxia 3.

Main Results:

  • Soluble mutant huntingtin represses CBP transcriptional activity early on.
  • Histone acetyltransferase activity of CBP/p300 diminishes over time.
  • Mutant huntingtin exhibits stronger binding to CBP, leading to its repression.
  • CBP protein levels are reduced via proteasome degradation in later stages.
  • p300 remains unaffected, and selective CBP degradation is absent in spinocerebellar ataxia 3.

Conclusions:

  • Mutant huntingtin selectively targets CBP, not p300, through multiple mechanisms.
  • Altered CBP/p300 ratios and reduced CBP levels contribute to chromatin and transcriptional dysregulation in HD.
  • These molecular disruptions play a role in the neurodegenerative process of Huntington's disease.

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