Transcriptional Abnormalities in Huntington's Disease

Dimitri Krainc*

*Corresponding author for this work

Research output: Chapter in Book/Report/Conference proceedingChapter


Huntington's disease (HD) is an inherited neurodegenerative disease caused by a glutamine repeat expansion in huntingtin protein. Transcriptional dysregulation has emerged as a potentially important pathogenic mechanism in HD. Regulation of transcription in eukaryotic cells involves an orchestrated interplay of chromatinpacked genes and protein complexes that control chromatin dynamics, transcriptional initiation, and transcription elongation. In HD, mutant huntingtin may interfere with several of these processes to cause transcriptional dysregulation. Mutant huntingtin-directed transcriptional repression involves gene-specific activator proteins such as Sp1 and CREB and selective components of the core transcription apparatus, including TFIID and TFIIF. In addition, the interference of chromatin modification by mutant huntingtin has been demonstrated through the use of histone deacetylase (HDAC) inhibitors. Deregulation of gene transcription by mutant huntingtin leads to repression of target genes involved in pathogenesis of HD such as dopamine D2 receptor. In addition, mutant huntingtin causes disruption of mitochondrial function by inhibiting gene expression of PGC-1a, a transcriptional co-activator that regulates several metabolic processes, including mitochondrial biogenesis and respiration. Mutant huntingtin represses PGC-1a expression by interfering with the CREB/TAF4 transcriptional pathway critical for the regulation of PGC-1a promoter. Inhibition of PGC-1a expression by mutant huntingtin leads to defects in energy metabolism and dysfunction of neurons that are most vulnerable to metabolic stress, such as striatum. Such disruption in energy homeostasis in HD may lead to early abnormalities in multiple cellular functions, and ultimately results in neurodegeneration. These studies suggest that transcriptional deregulation may occur before the development of disease symptoms in HD.

Original languageEnglish (US)
Title of host publicationTranscription Factors in the Nervous System
Subtitle of host publicationDevelopment, Brain Function, and Diseases
PublisherWiley-VCH Verlag GmbH & Co. KGaA
Number of pages24
ISBN (Print)3527312854, 9783527312856
StatePublished - May 22 2006


  • Deregulation of CRE-dependent transcription in HD
  • Disrupts Sp1-TAF4 transcriptional pathway
  • Mutant Huntingtin
  • Neuronal diseases
  • Transcription factors
  • Transcriptional abnormalities in Huntington's Disease

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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