Genetic deletion of transglutaminase 2 does not rescue the phenotypic deficits observed in R6/2 and zQ175 mouse models of Huntington's disease

PLoS One. 2014 Jun 23;9(6):e99520. doi: 10.1371/journal.pone.0099520. eCollection 2014.


Huntington's disease (HD) is an autosomal dominant, progressive neurodegenerative disorder caused by expansion of CAG repeats in the huntingtin gene. Tissue transglutaminase 2 (TG2), a multi-functional enzyme, was found to be increased both in HD patients and in mouse models of the disease. Furthermore, beneficial effects have been reported from the genetic ablation of TG2 in R6/2 and R6/1 mouse lines. To further evaluate the validity of this target for the treatment of HD, we examined the effects of TG2 deletion in two genetic mouse models of HD: R6/2 CAG 240 and zQ175 knock in (KI). Contrary to previous reports, under rigorous experimental conditions we found that TG2 ablation had no effect on either motor or cognitive deficits, or on the weight loss. In addition, under optimal husbandry conditions, TG2 ablation did not extend R6/2 lifespan. Moreover, TG2 deletion did not change the huntingtin aggregate load in cortex or striatum and did not decrease the brain atrophy observed in either mouse line. Finally, no amelioration of the dysregulation of striatal and cortical gene markers was detected. We conclude that TG2 is not a valid therapeutic target for the treatment of HD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Atrophy
  • Behavior, Animal
  • Brain / metabolism
  • Brain / pathology
  • Cognition Disorders / complications
  • Crosses, Genetic
  • Discrimination, Psychological
  • Disease Models, Animal
  • Female
  • GTP-Binding Proteins / genetics*
  • Gene Deletion*
  • Genotype
  • Huntington Disease / complications
  • Huntington Disease / enzymology*
  • Huntington Disease / pathology*
  • Ligands
  • Male
  • Maze Learning
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Neurologic Mutants
  • Phenotype
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Survival Analysis
  • Transglutaminases / genetics*
  • Weight Loss


  • Ligands
  • RNA, Messenger
  • transglutaminase 2
  • Transglutaminases
  • GTP-Binding Proteins

Grant support

CHDI Foundation is a privately-funded not-for-profit biomedical research organization exclusively dedicated to discovering and developing therapeutics that slow the progression of Huntington's disease. CHDI Foundation conducts research in a number of different ways; for the purposes of this manuscript, research was conducted at the contract research organizations PsychoGenics, Inc. and Charles River Discovery Research Services under a fee-for-service agreement, and at Kings College London under a sponsored research agreement. The authors listed all contributed to the conception, planning, and direction of the research; the specific roles of each author is outlined in the ‘author contributions’ section.