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

Abstract

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.

• Authors: Liliana B Menalled, Andrea E Kudwa, Steve Oakeshott, Andrew Farrar, Neil Paterson, Igor Filippov, Sam Miller, Mei Kwan, Michael Olsen, Jose Beltran, Justin Torello, Jon Fitzpatrick, Richard Mushlin, Kimberly Cox, Kristi McConnell, Matthew Mazzella, Dansha He, Georgina F Osborne, Rand Al-Nackkash, Gill P Bates, Pasi Tuunanen, Kimmo Lehtimaki, Dani Brunner, Afshin Ghavami, Sylvie Ramboz, Larry Park, Douglas Macdonald, Ignacio Munoz-Sanjuan, David Howland
• Journal: PloS one (PLoS One) Vol. 9 Issue 6 Pg. e99520 ( 2014) ISSN: 1932-6203 [Electronic] United States
• PMID: 24955833 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Ligands
• RNA, Messenger
• Protein Glutamine gamma Glutamyltransferase 2
• Transglutaminases
• GTP-Binding Proteins

Topics

• Animals
• Atrophy
• Behavior, Animal
• Brain (metabolism, pathology)
• Cognition Disorders (complications)
• Crosses, Genetic
• Discrimination, Psychological
• Disease Models, Animal
• Female
• GTP-Binding Proteins (genetics)
• Gene Deletion
• Genotype
• Huntington Disease (complications, enzymology, pathology)
• Ligands
• Male
• Maze Learning
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Neurologic Mutants
• Phenotype
• Protein Glutamine gamma Glutamyltransferase 2
• RNA, Messenger (genetics, metabolism)
• Survival Analysis
• Transglutaminases (genetics)
• Weight Loss