title: Generation and characterization of Dyt1 DeltaGAG knock-in mouse as a model for early-onset dystonia.
abstract: A trinucleotide deletion of GAG in the DYT1 gene that encodes torsinA protein is implicated in the neurological movement disorder of Oppenheim's early-onset dystonia. The mutation removes a glutamic acid in the carboxy region of torsinA, a member of the Clp protease/heat shock protein family. The function of torsinA and the role of the mutation in causing dystonia are largely unknown. To gain insight into these unknowns, we made a gene-targeted mouse model of Dyt1 DeltaGAG to mimic the mutation found in DYT1 dystonic patients. The mutated heterozygous mice had deficient performance on the beam-walking test, a measure of fine motor coordination and balance. In addition, they exhibited hyperactivity in the open-field test. Mutant mice also showed a gait abnormality of increased overlap. Mice at 3 months of age did not display deficits in beam-walking and gait, while 6-month mutant mice did, indicating an age factor in phenotypic expression as well. While striatal dopamine and 4-dihydroxyphenylacetic acid (DOPAC) levels in Dyt1 DeltaGAG mice were similar to that of wild-type mice, a 27% decrease in 4-hydroxy, 3-methoxyphenacetic acid (homovanillic acid) was detected in mutant mice. Dyt1 DeltaGAG tissues also have ubiquitin- and torsinA-containing aggregates in neurons of the pontine nuclei. A sex difference was noticed in the mutant mice with female mutant mice exhibiting fewer alterations in behavioral, neurochemical, and cellular changes. Our results show that knocking in a Dyt1 DeltaGAG allele in mouse alters their motor behavior and recapitulates the production of protein aggregates that are seen in dystonic patients. Our data further support alterations in the dopaminergic system as a part of dystonia's neuropathology.
authors.affiliation: Department of Molecular and Integrative Physiology, NeuroTech Group, Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
authors.forename: Mai T
authors.initials: MT
authors.lastname: Dang
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Yokoi
authors.forename: Kevin St P
authors.initials: KS
authors.lastname: McNaught
authors.forename: Toni-Ann
authors.initials: TA
authors.lastname: Jengelley
authors.forename: Tehone
authors.initials: T
authors.lastname: Jackson
authors.forename: Jianyong
authors.initials: J
authors.lastname: Li
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Li
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D017668:Age of Onset; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004421:Dystonia / Q000235:genetics* / Q000503:physiopathology*; D005260:Female; D005684:Gait / Q000235:genetics; D017353:Gene Deletion; D006719:Homovanillic Acid / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018832:Molecular Chaperones / Q000235:genetics* / Q000378:metabolism; D009043:Motor Activity / Q000235:genetics; D011597:Psychomotor Performance / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis; D011930:Reaction Time / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D045442:Rotarod Performance Test / Q000379:methods; D012737:Sex Factors; D025801:Ubiquitin / Q000378:metabolism
chemical_list: C491548:Dyt1 protein, mouse; D018832:Molecular Chaperones; D012333:RNA, Messenger; D025801:Ubiquitin; D015102:3,4-Dihydroxyphenylacetic Acid; D004298:Dopamine; D006719:Homovanillic Acid