Tissue transglutaminase overexpression does not modify the disease phenotype of the R6/2 mouse model of Huntington's disease

Kumar, Ashish; Kneynsberg, Andrew; Tucholski, Janusz; Perry, Giselle; Groen, Thomas van; Detloff, Peter J.; Lesort, Mathieu

doi:10.1016/j.expneurol.2012.05.015

Cited by 12 publications

(8 citation statements)

References 68 publications

(118 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Supporting our results, the overexpression of TG2 in R6/2 mice also did not modify the disease phenotype [43], raising additional questions about the role of TG2 activity in HD. The results of our genetic target validation work with a transglutaminase 2 null gene on the background of 2 different mouse models of HD do not support a therapeutic path aimed at TG2 inhibition for the treatment of HD.…”

Section: Discussionsupporting

confidence: 82%

“…In summary, under rigorous experimental conditions we found that the genetic ablation of TG2 does not ameliorate the disease phenotype, including physiological, molecular, neuropathological and behavioral markers in two different HD mouse models. Supporting our results, the overexpression of TG2 in R6/2 mice also did not modify the disease phenotype [43] , raising additional questions about the role of TG2 activity in HD. The results of our genetic target validation work with a transglutaminase 2 null gene on the background of 2 different mouse models of HD do not support a therapeutic path aimed at TG2 inhibition for the treatment of HD.…”

Section: Discussionsupporting

confidence: 82%

See 1 more Smart Citation

Genetic Deletion of Transglutaminase 2 Does Not Rescue the Phenotypic Deficits Observed in R6/2 and zQ175 Mouse Models of Huntington's Disease

et al. 2014

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 82%

Section: Discussionsupporting

confidence: 82%

Genetic Deletion of Transglutaminase 2 Does Not Rescue the Phenotypic Deficits Observed in R6/2 and zQ175 Mouse Models of Huntington's Disease

et al. 2014

View full text Add to dashboard Cite

show abstract

“…13 TG2 expression and transglutaminase activity have been shown to be increased in the brains of HD patients, 14 and in vitro and in vivo models have implicated TG2 in HD pathophysiology, 15−18 although more recent contradictory animal data have appeared. 19 The subject of irreversible inhibitors of TG2 has been recently reviewed. 20 Our studies have focused on irreversible inhibitors bearing an acrylamide warhead, 21,22 during which we became interested in dipeptides A and B 23 ( Figure 1) as leads due to their attractive potency and specificity for TG2.…”

mentioning

confidence: 99%

SAR Development of Lysine-Based Irreversible Inhibitors of Transglutaminase 2 for Huntington's Disease

Wityak

Prime

Brookfield

et al. 2012

ACS Med. Chem. Lett.

View full text Add to dashboard Cite

ABSTRACT:We report a series of irreversible transglutaminase 2 inhibitors starting from a known lysine dipeptide bearing an acrylamide warhead. We established new SARs resulting in compounds demonstrating improved potency and better physical and calculated properties. Transglutaminase selectivity profiling and in vitro ADME properties of selected compounds are also reported.KEYWORDS: plasma stability, polar surface area, acrylamides, celiac disease, in vitro ADME T issue transglutaminase 2 (TG2) is a multifunctional enzyme primarily known for its calcium-dependent protein cross-linking activity. 1 Less well-studied functions include simple amidase, GTPase, ATPase, and protein disulfide isomerase activities. 2−4 TG2 has been characterized in at least three forms, including open, 5 closed, 6 and an open-inactive form. 7 Genetic deletion of TG2 in mice suggests a role for TG2 activity in mitochondrial energy function, 8 and its overactivity has been most closely associated with celiac disease and Huntington's disease (HD). In addition, there is growing support for roles in inflammation and cancer. 9−12 HD is an autosomal dominant, progressive, neurodegenerative disease that is characterized clinically by motor, cognitive, and behavioral deficits. 13 TG2 expression and transglutaminase activity have been shown to be increased in the brains of HD patients, 14 and in vitro and in vivo models have implicated TG2 in HD pathophysiology, 15−18 although more recent contradictory animal data have appeared. 19 The subject of irreversible inhibitors of TG2 has been recently reviewed. 20 Our studies have focused on irreversible inhibitors bearing an acrylamide warhead, 21,22 during which we became interested in dipeptides A and B 23 (Figure 1) as leads due to their attractive potency and specificity for TG2. In a prior report, 21 we established that an excellent correlation exists for several transglutaminase isoforms between the IC 50 values using a 30 min compound incubation and the irreversible inhibition constants, k inact /K i . With this correlation in hand, we relied on the IC 50 values to guide our medicinal chemistry effort. We began by benchmarking dipeptide A, resulting in the selectivity profile illustrated in Figure 1. We also resynthesized and tested several compounds from the Marrano paper, 23 the results of which are found in the Supporting Information. To summarize, the results confirmed that dipeptide A was one of the most potent TG2 inhibitors from this report. As shown in Figure 1, ADME profiling studies on this compound indicated good solubility, low permeability potentially accompanied by efflux, and rapid metabolism in mouse liver microsomes (mLM). Our goal was to identify a tool molecule from this series for in vivo proof of concept studies in HD, where brain is the target organ. Therefore, we focused on increasing potency, improving the absorption profile, and increasing microsomal stability. Lowering the polar surface area (PSA), the number of hydrogen bond donors, and the number of rotatable bon...

show abstract

“…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.…”

Section: Cell Adhesion and Spreadingmentioning

confidence: 99%

Insights into Transglutaminase 2 Function Gained from Genetically Modified Animal Models

Iismaa

2015

Transglutaminases

View full text Add to dashboard Cite

Transglutaminase 2 (TG2) has been implicated in a number of physiological processes and in disease. A number of different types of genetically engineered mice have been generated to help understand the role and regulation of TG2 in physiology and pathology and to help delineate the molecular basis of its actions. This chapter will briefly review guidelines for animal husbandry and animal study design, TG2 mouse models and recent insights into the physiology and pathophysiology of TG2 that have come from the study of these genetically engineered animal models.

show abstract

Tissue transglutaminase overexpression does not modify the disease phenotype of the R6/2 mouse model of Huntington's disease

Cited by 12 publications

References 68 publications

Genetic Deletion of Transglutaminase 2 Does Not Rescue the Phenotypic Deficits Observed in R6/2 and zQ175 Mouse Models of Huntington's Disease

Genetic Deletion of Transglutaminase 2 Does Not Rescue the Phenotypic Deficits Observed in R6/2 and zQ175 Mouse Models of Huntington's Disease

SAR Development of Lysine-Based Irreversible Inhibitors of Transglutaminase 2 for Huntington's Disease

Insights into Transglutaminase 2 Function Gained from Genetically Modified Animal Models

Contact Info

Product

Resources

About