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Expanded polyglutamine stretches interact with TAFII130, interfering with CREB-dependent transcription

T Shimohata1, T Nakajima, M Yamada

  • 1Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan.

Nature Genetics
|September 6, 2000
PubMed

Insights

Expanded polyglutamine (polyQ) stretches in neurodegenerative diseases bind to TAFII130, suppressing gene transcription. Restoring TAFII130 levels can reverse this suppression and cell death, revealing a key mechanism in neurodegeneration.

Area of Science:

  • Molecular Biology
  • Neuroscience
  • Genetics

Background:

  • Inherited neurodegenerative diseases are linked to expanded CAG repeats forming polyglutamine (polyQ) stretches.
  • The precise molecular mechanisms driving neurodegeneration due to these expanded polyQ stretches are not fully understood.

Purpose of the Study:

  • To investigate the molecular interactions and functional consequences of expanded polyQ stretches in neurodegeneration.
  • To identify the specific cellular targets and pathways affected by polyQ expansion.

Main Methods:

  • Investigated the binding interactions between expanded polyQ stretches and cellular proteins.
  • Assessed the impact of polyQ expansion on transcriptional activation, specifically CREB-dependent pathways.
  • Utilized co-expression systems to evaluate rescue effects.

Main Results:

  • Expanded polyQ stretches demonstrate a preferential binding affinity for TAFII130, a crucial coactivator for CREB-dependent transcription.
  • This binding leads to a significant suppression of CREB-dependent transcriptional activity.
  • Co-expression of TAFII130 successfully restored both the suppressed transcription and the polyQ-induced cell death.

Conclusions:

  • The binding of expanded polyQ stretches to TAFII130 interferes with CREB-dependent transcription.
  • This transcriptional interference is a key factor in the pathogenesis of polyQ-mediated neurodegenerative diseases.
  • Targeting the TAFII130-polyQ interaction may offer therapeutic strategies for these conditions.

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