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Activation of the IkappaB kinase complex and nuclear factor-kappaB contributes to mutant huntingtin neurotoxicity.

Transcriptional dysregulation by mutant huntingtin (Htt) protein has been implicated in the pathogenesis of Huntington's disease (HD). We find that cultured cells expressing mutant Htt and striatal cells from HD transgenic mice have elevated nuclear factor-kappaB (NF-kappaB) activity. Furthermore, NF-kappaB is concentrated in the nucleus of neurons in the brains of HD transgenic mice. In inducible PC12 cells and in HD transgenic mice, mutant Htt activates the IkappaB kinase complex (IKK), a key regulator of NF-kappaB. Activation of IKK is likely mediated by direct interaction with mutant Htt, because the expanded polyglutamine stretch and adjacent proline-rich motifs in mutant Htt interact with IKKgamma, a regulatory subunit of IKK. Activation of IKK may also influence the toxicity of mutant Htt, because expression of IKKgamma promotes aggregation and nuclear localization of mutant Htt exon-1. Moreover, in acute striatal slice cultures, inhibition of IKK activity with an N-terminally truncated form of IKKgamma blocks mutant Htt-induced toxicity in medium-sized spiny neurons (MSNs). In addition, blocking degradation of NF-kappaB inhibitors with a dominant-negative ubiquitin ligase beta-transducin repeat-containing protein also reduces the toxicity of mutant Htt in MSNs. Therefore, aberrant NF-kappaB activation may contribute to the neurodegeneration induced by mutant Htt.

Pubmed ID: 15371500


  • Khoshnan A
  • Ko J
  • Watkin EE
  • Paige LA
  • Reinhart PH
  • Patterson PH


The Journal of neuroscience : the official journal of the Society for Neuroscience

Publication Data

September 15, 2004

Associated Grants

  • Agency: NINDS NIH HHS, Id: NS045165-01A1

Mesh Terms

  • Amino Acid Motifs
  • Animals
  • Biolistics
  • Cell Line
  • Cell Line, Transformed
  • Corpus Striatum
  • Enzyme Activation
  • Exons
  • Gene Expression Regulation
  • Genes, Reporter
  • Humans
  • I-kappa B Kinase
  • Interleukin-1
  • Kidney
  • Mice
  • Mice, Transgenic
  • Minisatellite Repeats
  • NF-kappa B
  • Nerve Degeneration
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • PC12 Cells
  • Phosphorylation
  • Protein Binding
  • Protein Interaction Mapping
  • Protein Processing, Post-Translational
  • Protein-Serine-Threonine Kinases
  • Rats
  • Rats, Sprague-Dawley
  • Recombinant Fusion Proteins
  • Transfection
  • Ubiquitin-Protein Ligases