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Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes.

Huntingtin protein is mutated in Huntington disease. We previously reported that wild-type but not mutant huntingtin stimulates transcription of the gene encoding brain-derived neurotrophic factor (BDNF; ref. 2). Here we show that the neuron restrictive silencer element (NRSE) is the target of wild-type huntingtin activity on BDNF promoter II. Wild-type huntingtin inhibits the silencing activity of NRSE, increasing transcription of BDNF. We show that this effect occurs through cytoplasmic sequestering of repressor element-1 transcription factor/neuron restrictive silencer factor (REST/NRSF), the transcription factor that binds to NRSE. In contrast, aberrant accumulation of REST/NRSF in the nucleus is present in Huntington disease. We show that wild-type huntingtin coimmunoprecipitates with REST/NRSF and that less immunoprecipitated material is found in brain tissue with Huntington disease. We also report that wild-type huntingtin acts as a positive transcriptional regulator for other NRSE-containing genes involved in the maintenance of the neuronal phenotype. Consistently, loss of expression of NRSE-controlled neuronal genes is shown in cells, mice and human brain with Huntington disease. We conclude that wild-type huntingtin acts in the cytoplasm of neurons to regulate the availability of REST/NRSF to its nuclear NRSE-binding site and that this control is lost in the pathology of Huntington disease. These data identify a new mechanism by which mutation of huntingtin causes loss of transcription of neuronal genes.

Pubmed ID: 12881722


  • Zuccato C
  • Tartari M
  • Crotti A
  • Goffredo D
  • Valenza M
  • Conti L
  • Cataudella T
  • Leavitt BR
  • Hayden MR
  • Timmusk T
  • Rigamonti D
  • Cattaneo E


Nature genetics

Publication Data

September 29, 2003

Associated Grants

  • Agency: Telethon, Id: E.0840

Mesh Terms

  • Animals
  • Brain-Derived Neurotrophic Factor
  • Cell Line
  • Gene Expression Regulation
  • Humans
  • Huntington Disease
  • Mice
  • Mice, Knockout
  • Nerve Tissue Proteins
  • Neurons
  • Nuclear Proteins
  • Promoter Regions, Genetic
  • Rats
  • Rats, Sprague-Dawley
  • Repressor Proteins
  • Silencer Elements, Transcriptional
  • Transcription Factors
  • Transcription, Genetic