By live cell fluorescence lifetime imaging measurement-Förster resonant energy transfer studies and western blot assays, we quantitatively observed that stress-activated tissue transglutaminase 2 (TG2) is responsible for the actin-cofilin covalent cross-linking observed in HD.
The authors find that TG2 inhibition can ameliorate HD neurodegeneration, and thereby elevate the status of transglutaminases (TGs) to a major therapeutic target-not because of their well-known activity in mutant protein aggregation, but instead based upon their ability to epigenetically modulate transcription and energy production.
So far, increased levels and activity of tissue transglutaminase (tTG), the best characterized member of the TG family, have been observed in many neurodegenerative diseases, and the self-interacting proteins, characteristic of Alzheimer's disease, Parkinson's disease and Huntington's disease, are known substrates of tTG.
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.
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.
Mitochondrial aconitase is a transglutaminase 2 substrate: transglutamination is a probable mechanism contributing to high-molecular-weight aggregates of aconitase and loss of aconitase activity in Huntington disease brain.
Since mouse models are currently being used to study the role of tTG in Huntington's disease and other neurodegenerative diseases, it is critical that the level of its expression in the mouse forebrain be determined.
Furthermore, the transglutaminase 2 isoform colocalizes with both huntingtin protein and epsilon-(gamma-glutamyl) lysine covalent cross-links in HD intranuclear inclusions.
Because in vitro expanded polyglutamine repeats are excellent glutaminyl-donor substrates of tissue transglutaminase (tTG), it has been hypothesized that tTG may contribute to the formation of these aggregates in HD.
Tissue transglutaminase (tTG) is a transamidating enzyme that is elevated in Huntington's disease (HD) brain and may be involved in the etiology of the disease.
Recent findings have provided evidence that dysregulation of tissue transglutaminase may contribute to the pathology of several neurodegenerative conditions including Alzheimer's disease and Huntington's disease.