Figure 1. Model for action of transglutamine 2 in Huntington's disease.

1. Under normal conditions, transglutaminase 2 (TG2) activity is at baseline and does not interfere with transcription of key genes involved in the regulation of mitochondrial and metabolic functions, such as PGC-1α.
2. In Huntington's disease, TG2 activity increases, resulting in polyamination of histones yielding an increased net positive charge that promotes tighter packing of DNA with histones. This alteration of chromatin structure can repress the transcription of target genes. Reduced expression from PGC-1α and related genes thus contributes to the mitochondrial and metabolic dysfunction characteristic of Huntington's disease.