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

Liliana Menalled ,Sylvie Ramboz,Kimberly Cox,Mei Kwan,Andrea E Kudwa,Dani Brunner,Afshin Ghavami,Justin Torello,Michael Olsen,Steve Oakeshott,David Howland,Richard Mushlin,Larry Park,Pasi Tuunanen,Sam Miller,Kristi Mcconnell,Douglas Macdonald,José Eduardo Padilla Beltrán ,R Al-Nackkash ,Di He ,Matthew J Mazzella ,Andrew M Farrar ,Neil E Paterson ,John E Fitzpatrick ,I K Filippov ,Gillian P Bates ,Georgina F Osborne ,Ignacio Muñoz-Sanjuán ,Kimmo Lehtimäki

doi:10.1371/journal.pone.0099520

Liliana Menalled , Sylvie Ramboz + Show 27 more

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https://doi.org/10.1371/journal.pone.0099520

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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.

Highlights

Tissue transglutaminase 2 (TG2; TGM2; human Gene ID# 7052) is a multi-functional enzyme primarily known for its calcium-dependent intra- and intermolecular cross-linking activity via isopeptide bond formation between glutamine and lysine residues [1]
We employed a genetic deletion approach to further examine the possible role that TG2 plays in Huntington’s disease (HD)
We further examined the effect of the TG2 ablation using molecular and imaging techniques

Summary

Introduction

Tissue transglutaminase 2 (TG2; TGM2; human Gene ID# 7052) is a multi-functional enzyme primarily known for its calcium-dependent intra- and intermolecular cross-linking activity via isopeptide bond formation between glutamine and lysine residues [1]. Genetic deletion of TG2 in mice has suggested a role for TG2 activity in mitochondrial energy function [5]. HD is a genetic, autosomal dominant, progressive neurodegenerative disorder caused by the expansion of the CAG trinucleotide repeat found in the huntingtin gene; when the repeat number exceeds 39, individuals will develop HD within an normal lifespan [10]. The disorder is characterized by motor and cognitive deficits as well as, psychiatric problems. The disorder is characterized by striatal and cortical atrophy, formation of intracellular huntingtin aggregates, and gene expression changes [10]

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