title: 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.
authors: PsychoGenics Inc., Tarrytown, New York, United States of America.
authors: Liliana B
authors: LB
authors: Menalled
authors: PsychoGenics Inc., Tarrytown, New York, United States of America.
authors: Andrea E
authors: AE
authors: Kudwa
authors: PsychoGenics Inc., Tarrytown, New York, United States of America.
authors: Steve
authors: S
authors: Oakeshott
authors: PsychoGenics Inc., Tarrytown, New York, United States of America.
authors: Andrew
authors: A
authors: Farrar
authors: PsychoGenics Inc., Tarrytown, New York, United States of America.
authors: Neil
authors: N
authors: Paterson
authors: PsychoGenics Inc., Tarrytown, New York, United States of America.
authors: Igor
authors: I
authors: Filippov
authors: PsychoGenics Inc., Tarrytown, New York, United States of America.
authors: Sam
authors: S
authors: Miller
authors: PsychoGenics Inc., Tarrytown, New York, United States of America.
authors: Mei
authors: M
authors: Kwan
authors: PsychoGenics Inc., Tarrytown, New York, United States of America.
authors: Michael
authors: M
authors: Olsen
authors: PsychoGenics Inc., Tarrytown, New York, United States of America.
authors: Jose
authors: J
authors: Beltran
authors: PsychoGenics Inc., Tarrytown, New York, United States of America.
authors: Justin
authors: J
authors: Torello
authors: PsychoGenics Inc., Tarrytown, New York, United States of America.
authors: Jon
authors: J
authors: Fitzpatrick
authors: PsychoGenics Inc., Tarrytown, New York, United States of America.
authors: Richard
authors: R
authors: Mushlin
authors: PsychoGenics Inc., Tarrytown, New York, United States of America.
authors: Kimberly
authors: K
authors: Cox
authors: PsychoGenics Inc., Tarrytown, New York, United States of America.
authors: Kristi
authors: K
authors: McConnell
authors: PsychoGenics Inc., Tarrytown, New York, United States of America.
authors: Matthew
authors: M
authors: Mazzella
authors: PsychoGenics Inc., Tarrytown, New York, United States of America.
authors: Dansha
authors: D
authors: He
authors: Department of Medical and Molecular Genetics, King's College London, London, United Kingdom.
authors: Georgina F
authors: GF
authors: Osborne
authors: Department of Medical and Molecular Genetics, King's College London, London, United Kingdom.
authors: Rand
authors: R
authors: Al-Nackkash
authors: Department of Medical and Molecular Genetics, King's College London, London, United Kingdom.
authors: Gill P
authors: GP
authors: Bates
authors: Charles River Discovery Research Services, Kuopio, Finland.
authors: Pasi
authors: P
authors: Tuunanen
authors: Charles River Discovery Research Services, Kuopio, Finland.
authors: Kimmo
authors: K
authors: Lehtimaki
authors: PsychoGenics Inc., Tarrytown, New York, United States of America.
authors: Dani
authors: D
authors: Brunner
authors: PsychoGenics Inc., Tarrytown, New York, United States of America.
authors: Afshin
authors: A
authors: Ghavami
authors: PsychoGenics Inc., Tarrytown, New York, United States of America.
authors: Sylvie
authors: S
authors: Ramboz
authors: CHDI Management/CHDI Foundation, Princeton, New Jersey, United States of America.
authors: Larry
authors: L
authors: Park
authors: CHDI Management/CHDI Foundation, Princeton, New Jersey, United States of America.
authors: Douglas
authors: D
authors: Macdonald
authors: CHDI Management/CHDI Foundation, Princeton, New Jersey, United States of America.
authors: Ignacio
authors: I
authors: Munoz-Sanjuan
authors: CHDI Management/CHDI Foundation, Princeton, New Jersey, United States of America.
authors: David
authors: D
authors: Howland
mesh_terms: D000818:Animals; D001284:Atrophy; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism / Q000473:pathology; D003072:Cognition Disorders / Q000150:complications; D003433:Crosses, Genetic; D004192:Discrimination, Psychological; D004195:Disease Models, Animal; D005260:Female; D019204:GTP-Binding Proteins / Q000235:genetics*; D017353:Gene Deletion; D005838:Genotype; D006816:Huntington Disease / Q000150:complications / Q000201:enzymology* / Q000473:pathology*; D008024:Ligands; D008297:Male; D018782:Maze Learning; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008818:Mice, Neurologic Mutants; D010641:Phenotype; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D011503:Transglutaminases / Q000235:genetics*; D015431:Weight Loss
chemical_list: D008024:Ligands; D012333:RNA, Messenger; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins