Interference with activity-dependent transcriptional activation of BDNF gene depending upon the expanded polyglutamines in neurons

Biochem Biophys Res Commun. 2005 Aug 12;333(4):1241-8. doi: 10.1016/j.bbrc.2005.06.032.

Abstract

Expanded polyglutamines (polyQ) have been demonstrated to impair the CREB-dependent transcription in established cell lines. Since activity-dependent transcription in neurons, which plays an important role in forming neuronal plasticity, is largely controlled by CREB, it is important to study whether polyQ interferes with the activity-dependent transcriptional activation of genes in neurons. In cultured rat cortical neurons, over-expression of truncated dentatorubral-pallidoluysian atrophy proteins containing expanded polyQ, which form aggregation bodies in nucleus, reduced the calcium (Ca(2+)) signal-mediated transcriptional activation of brain-derived neurotrophic factor, c-fos, and pituitary adenylate cyclase-activating polypeptide gene promoters in a dose-dependent manner. The interference with the transcriptional activation was dependent upon the presence of polyQ, the strength of which was increased as the length of polyQ stretches was expanded. Thus, polyQ interferes with the activity-dependent transcription in a polyQ-length-dependent manner, which may correspond to the severity of polyglutamine diseases.

MeSH terms

  • Animals
  • Brain-Derived Neurotrophic Factor / genetics*
  • Brain-Derived Neurotrophic Factor / metabolism*
  • Calcium / metabolism
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Cerebral Cortex / embryology
  • Cerebral Cortex / metabolism
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism*
  • Neurons / metabolism*
  • Peptides / genetics*
  • Peptides / metabolism*
  • Promoter Regions, Genetic / genetics
  • Rats
  • Rats, Sprague-Dawley
  • Transcriptional Activation / physiology*

Substances

  • Brain-Derived Neurotrophic Factor
  • Nerve Tissue Proteins
  • Peptides
  • atrophin-1
  • polyglutamine
  • Calcium