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

Menalled LB, Kudwa AE, Oakeshott S, Farrar A, Paterson N, Filippov I, Miller S, Kwan M, Olsen M, Beltran J, Torello J, Fitzpatrick J, Mushlin R, Cox K, McConnell K, Mazzella M, He D, Osborne GF, Al-Nackkash R, Bates GP, Tuunanen P, Lehtimaki K, Brunner D, Ghavami A, Ramboz S, Park L, Macdonald D, Munoz-Sanjuan I, Howland D - PLoS ONE (2014)

Bottom Line: 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.We conclude that TG2 is not a valid therapeutic target for the treatment of HD.

View Article: PubMed Central - PubMed

Affiliation: PsychoGenics Inc., Tarrytown, New York, United States of America.

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.

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Overall visit frequency detected in the PhenoCube system as a function of genotype, age and light cycle phase in animals from the zQ175×TG2 KO line.*Significant HD genotype differences regardless of the light phase (in the mean path length the differences were detected between HET and WT animals); ##significant differences due to light phase in the cycle independently of genotype; ∧significant TG2 genotype differences (see results method for details). WT: wild-type, TG2−/−: homozygous TG2 knockout, HET: zQ175 HET, HOM: zQ175 HOM.
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pone-0099520-g004: Overall visit frequency detected in the PhenoCube system as a function of genotype, age and light cycle phase in animals from the zQ175×TG2 KO line.*Significant HD genotype differences regardless of the light phase (in the mean path length the differences were detected between HET and WT animals); ##significant differences due to light phase in the cycle independently of genotype; ∧significant TG2 genotype differences (see results method for details). WT: wild-type, TG2−/−: homozygous TG2 knockout, HET: zQ175 HET, HOM: zQ175 HOM.

Mentions: Overall visit frequency: Both zQ175 HOM and HET mice showed a significantly decreased visit frequency when compared to the WT mice (Figure 4; HD Genotype main effect: F(2,110) = 6.72, p<0.005). The absence of the TG2 protein produced a small but significant increase of activity in HOM male mice, in the dark phase of the cycle. In both female and male WT mice, the effect was, instead, a significant decrease, observed during both phases in females but only in the dark phase in males (HD Genotype×TG2 Genotype×Sex×Cycle interaction: F(2,16) = 4.11, p<0.05; simple main effects and post hocs, ps<0.05). As expected, a marked increase in corner visit frequency during the dark versus the light periods was observed in all mice regardless of the genotype and sex (Cycle main effect: F(1,110) = 802.22, p<0.0001).


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

Menalled LB, Kudwa AE, Oakeshott S, Farrar A, Paterson N, Filippov I, Miller S, Kwan M, Olsen M, Beltran J, Torello J, Fitzpatrick J, Mushlin R, Cox K, McConnell K, Mazzella M, He D, Osborne GF, Al-Nackkash R, Bates GP, Tuunanen P, Lehtimaki K, Brunner D, Ghavami A, Ramboz S, Park L, Macdonald D, Munoz-Sanjuan I, Howland D - PLoS ONE (2014)

Overall visit frequency detected in the PhenoCube system as a function of genotype, age and light cycle phase in animals from the zQ175×TG2 KO line.*Significant HD genotype differences regardless of the light phase (in the mean path length the differences were detected between HET and WT animals); ##significant differences due to light phase in the cycle independently of genotype; ∧significant TG2 genotype differences (see results method for details). WT: wild-type, TG2−/−: homozygous TG2 knockout, HET: zQ175 HET, HOM: zQ175 HOM.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4067284&req=5

pone-0099520-g004: Overall visit frequency detected in the PhenoCube system as a function of genotype, age and light cycle phase in animals from the zQ175×TG2 KO line.*Significant HD genotype differences regardless of the light phase (in the mean path length the differences were detected between HET and WT animals); ##significant differences due to light phase in the cycle independently of genotype; ∧significant TG2 genotype differences (see results method for details). WT: wild-type, TG2−/−: homozygous TG2 knockout, HET: zQ175 HET, HOM: zQ175 HOM.
Mentions: Overall visit frequency: Both zQ175 HOM and HET mice showed a significantly decreased visit frequency when compared to the WT mice (Figure 4; HD Genotype main effect: F(2,110) = 6.72, p<0.005). The absence of the TG2 protein produced a small but significant increase of activity in HOM male mice, in the dark phase of the cycle. In both female and male WT mice, the effect was, instead, a significant decrease, observed during both phases in females but only in the dark phase in males (HD Genotype×TG2 Genotype×Sex×Cycle interaction: F(2,16) = 4.11, p<0.05; simple main effects and post hocs, ps<0.05). As expected, a marked increase in corner visit frequency during the dark versus the light periods was observed in all mice regardless of the genotype and sex (Cycle main effect: F(1,110) = 802.22, p<0.0001).

Bottom Line: 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.We conclude that TG2 is not a valid therapeutic target for the treatment of HD.

View Article: PubMed Central - PubMed

Affiliation: PsychoGenics Inc., Tarrytown, New York, United States of America.

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.

Show MeSH
Related in: MedlinePlus