Transglutaminase cross-links in intranuclear inclusions in huntington disease

Gina M. Zainelli, Christopher A. Ross, Juan C. Troncoso, Nancy A. Muma

Research output: Contribution to journalArticlepeer-review

78 Scopus citations


Cortical and striatal perinuclear cytoplasmic aggregates and intranuclear inclusions of mutant huntingtin are neuropathological hallmarks of Huntington disease (HD). Although the mechanisms involved in the formation of these aggregates are unclear, a recent hypothesis implicates cross-linking of mutant huntingtin protein into aggregates by transglutaminase. This study explores the hypothesis that transglutaminase catalyzes cross-linking of huntingtin into intranuclear inclusions. Using immunofluorescence and confocal microscopy we demonstrate 99% colocalization of transglutaminase-catalyzed ε-(γglutamyl) lysine covalent cross-links with nuclear aggregates of huntingtin protein in the frontal cortex of postmortem HD brain tissue. Furthermore, the transglutaminase 2 isoform colocalizes with both huntingtin protein and ε-(γ-glutamyl) lysine covalent cross-links in HD intranuclear inclusions. Transient transfection of N-terminally truncated huntingtin with an expanded glutamine domain (htt-N63-148Q-myc) with and without and transglutaminase 2 into HEK 293T cells resulted in an increase in cross-linked huntingtin in the insoluble formic acid-treated pellet in comparison to transfection of N-terminally truncated huntingtin with normal length glutamine domain (htt-N63-18Q-myc). Transfection with both htt-N63-148Q-myc and transglutaminase 2 resulted in high molecular weight huntingtin in the insoluble fraction. These data support the hypothesis that transglutaminase catalyzed cross-linking of mutant huntingtin is involved in the formation and/or stabilization of huntingtin protein aggregates in HD. Based on these and other studies, modulation of transglutaminase activity could be explored as a treatment for HD.

Original languageEnglish (US)
Pages (from-to)14-24
Number of pages11
JournalJournal of neuropathology and experimental neurology
Issue number1
StatePublished - Jan 1 2003


  • Huntingtin
  • Huntington disease (HD)
  • Intranuclear inclusions
  • Isodipeptide bond
  • Neurodegeneration
  • Transglutaminase
  • ε-(γ-glutamyl) lysine cross-links

ASJC Scopus subject areas

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


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