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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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Behavioral data captured in the PhenoCube system as a function of genotype, age and light cycle phase in animals from the R6/2×TG2 KO line.A. Overall visit frequency. B. Mean path length. C. Percent alternations (Data for this measure were not collected at 16 weeks of age since R6/2 mice were not tested in this protocol due to reduced licking). *Significant HD genotype differences within each light phase, at each age; #: significant differences due to light phase in the diurnal cycle in the WT mice; ##significant differences due to light phase in the cycle for each age independently of genotype; ###significant differences due to light phase in the diurnal cycle in the R6/2 mice; ∧significant TG2 genotype differences. WT: wild-type, TG2+/−: heterozygous TG2 knockout, TG2−/−: homozygous TG2 knockout.
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pone-0099520-g003: Behavioral data captured in the PhenoCube system as a function of genotype, age and light cycle phase in animals from the R6/2×TG2 KO line.A. Overall visit frequency. B. Mean path length. C. Percent alternations (Data for this measure were not collected at 16 weeks of age since R6/2 mice were not tested in this protocol due to reduced licking). *Significant HD genotype differences within each light phase, at each age; #: significant differences due to light phase in the diurnal cycle in the WT mice; ##significant differences due to light phase in the cycle for each age independently of genotype; ###significant differences due to light phase in the diurnal cycle in the R6/2 mice; ∧significant TG2 genotype differences. WT: wild-type, TG2+/−: heterozygous TG2 knockout, TG2−/−: homozygous TG2 knockout.

Mentions: Overall visit frequency: R6/2 showed a progressive age-related decrease in activity when compared to WTs in all the phases of the diurnal cycle with the exception of 8 week old mice during the light phase (Figure 3A; HD Genotype×Cycle×Age interaction: F(2,319) = 16.50, p<0.0001; simple main effects and post hocs, ps<0.05). Both partial or complete reduction of the TG2 protein expression produced a decrease in overall visit frequency during the dark phase regardless of the status of the R6/2 transgene, mainly driven by male mice at 8 and 12 weeks of age (not shown, TG2 Genotype×Cycle interaction: F(2, 177) = 4.24, p<0.05, simple main effect and post hocs, ps<0.05; TG2 Genotype×Age×Sex interaction: F(4,301) = 3.3, p<0.05; simple main effects and post hocs, ps<0.05). As expected, mice displayed a marked increase in corner visit frequency during the dark versus light periods of the diurnal cycle irrespectively of the genotype (Cycle main effect: F(1,133) = 433.07, 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)

Behavioral data captured in the PhenoCube system as a function of genotype, age and light cycle phase in animals from the R6/2×TG2 KO line.A. Overall visit frequency. B. Mean path length. C. Percent alternations (Data for this measure were not collected at 16 weeks of age since R6/2 mice were not tested in this protocol due to reduced licking). *Significant HD genotype differences within each light phase, at each age; #: significant differences due to light phase in the diurnal cycle in the WT mice; ##significant differences due to light phase in the cycle for each age independently of genotype; ###significant differences due to light phase in the diurnal cycle in the R6/2 mice; ∧significant TG2 genotype differences. WT: wild-type, TG2+/−: heterozygous TG2 knockout, TG2−/−: homozygous TG2 knockout.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0099520-g003: Behavioral data captured in the PhenoCube system as a function of genotype, age and light cycle phase in animals from the R6/2×TG2 KO line.A. Overall visit frequency. B. Mean path length. C. Percent alternations (Data for this measure were not collected at 16 weeks of age since R6/2 mice were not tested in this protocol due to reduced licking). *Significant HD genotype differences within each light phase, at each age; #: significant differences due to light phase in the diurnal cycle in the WT mice; ##significant differences due to light phase in the cycle for each age independently of genotype; ###significant differences due to light phase in the diurnal cycle in the R6/2 mice; ∧significant TG2 genotype differences. WT: wild-type, TG2+/−: heterozygous TG2 knockout, TG2−/−: homozygous TG2 knockout.
Mentions: Overall visit frequency: R6/2 showed a progressive age-related decrease in activity when compared to WTs in all the phases of the diurnal cycle with the exception of 8 week old mice during the light phase (Figure 3A; HD Genotype×Cycle×Age interaction: F(2,319) = 16.50, p<0.0001; simple main effects and post hocs, ps<0.05). Both partial or complete reduction of the TG2 protein expression produced a decrease in overall visit frequency during the dark phase regardless of the status of the R6/2 transgene, mainly driven by male mice at 8 and 12 weeks of age (not shown, TG2 Genotype×Cycle interaction: F(2, 177) = 4.24, p<0.05, simple main effect and post hocs, ps<0.05; TG2 Genotype×Age×Sex interaction: F(4,301) = 3.3, p<0.05; simple main effects and post hocs, ps<0.05). As expected, mice displayed a marked increase in corner visit frequency during the dark versus light periods of the diurnal cycle irrespectively of the genotype (Cycle main effect: F(1,133) = 433.07, 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