Mutant huntingtin protein: A substrate for transglutaminase 1, 2, and 3

Gina M. Zainelli, Nichole L. Dudek, Christopher A. Ross, Soo Youl Kim, Nancy A. Muma

Research output: Contribution to journalArticlepeer-review

47 Scopus citations


The most prominent neuropathologic hallmarks of Huntington disease (HD) are cortical and striatal perinuclear cytoplasmic aggregates and intranuclear inclusions of mutant huntingtin. Our laboratory previously demonstrated that huntingtin protein colocalizes with transglutaminase 2 and its product, the ε-(γ-glutamyl)lysine bond in intranuclear inclusions in HD frontal cortex. We also found that transglutaminase 2 cross-links N-terminal fragments of mutant huntingtin (htt-N63-148Q-myc) in cells in culture. We now report a significant increase in transglutaminase 2 mRNA in HD cortex (225% of controls) and striatum (399% of controls). Expression of the short transglutaminase 2 mRNA splice variant was not detectable in HD, although previous studies demonstrated upregulation in Alzheimer disease and progressive supranuclear palsy. Cells co-transfected with GFP-tagged transglutaminase 1, 2, or 3 and htt-N63-148Q-myc exhibit increased cross-linked huntingtin in the insoluble fraction of cell lysates. Treatment of cells with cystamine, a chemical inhibitor of transglutaminase, decreased aggregated and cross-linked huntingtin and increased viability of cells that were transfected with transglutaminase 2 and htt-N63-148Q-myc. These data suggest that transglutaminase 1, 2, and 3 could be involved in cross-linking of huntingtin into intranuclear inclusions in HD and that inhibiting transglutaminase should be explored as a potential treatment strategy for HD.

Original languageEnglish (US)
Pages (from-to)58-65
Number of pages8
JournalJournal of neuropathology and experimental neurology
Issue number1
StatePublished - Jan 2005


  • Aggregation
  • Cell death
  • Cross-linking
  • Huntingtin
  • Huntington disease
  • Transglutaminase

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Neurology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience


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