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.

TAK-063, a Novel Phosphodiesterase 10A Inhibitor, Protects from Striatal Neurodegeneration and Ameliorates Behavioral Deficits in the R6/2 Mouse Model of Huntington’s Disease

“…To investigate procedural learning and cognitive flexibility, procedural water T-maze test was performed using a T-shaped water maze in mice at 9-10 weeks of age (Tanimura et al, 2008;Menalled et al, 2014). T-maze test was conducted in a room at approximately 15 lux.…”

Transglutaminase Activity as a Possible Molecular Mechanism in the Etiopathogenesis of Neurodegenerative Diseases

“…Therefore, from a number of standpoints it would seem that a selective inhibitor, which discriminates between TGs, would be preferable to an indiscriminate TG inhibitor. In fact, although most of the TG activity in mouse brain, at least as assessed by an assay that measures the incorporation of radioactive putrescine (amine donor) into N, N-dimethyl casein (amine acceptor), seems to be due to TG2 [85] , no conclusive data have been obtained by TG2 gene knock-out experiments about the involvement of this TG in the development of the symptoms in HDtransgenic mice [26,86,87] . Moreover, a recent scientific report showed that cystamine reduces aggregate formation in a mouse model of oculopharyngeal muscular dystrophy (OMPD), in which also the TG2 knockdown is capable of suppressing the aggregation and the toxicity of the mutant protein PABPN1 [88] , suggesting this compound as a possible therapeutic for OMPD.…”

Insights into Transglutaminase 2 Function Gained from Genetically Modified Animal Models

“…In contrast, constitutive TG2 overexpression in B6 mouse neurons (Tucholski et al 2006) did not modify disease onset or progression in R6/2 on a B6 background (R6/2B) (Kumar et al 2012). Nor did genetic deletion of TG2 [ (Nanda et al 2001) backcrossed 12 generations to B6] in two different HD models, where experiments were performed according to the recommended guidelines for animal husbandry and study design (Menalled et al 2014b), calling into question the role of TG2 in HD.…”