Impaired motor learning in mice expressing torsinA with the DYT1 dystonia mutation.
Primary early-onset generalized dystonia is an autosomal dominant disorder caused by a deletion (DeltaGAG) in the DYT1 gene encoding torsinA. The gene defect has incomplete penetrance, with approximately 30% of carriers developing clinically evident dystonia. We describe lines of transgenic mice that express either human mutant torsinA (hMT) or human wild-type (hWT) torsinA. All mice demonstrated moderately increased levels of torsinA in the brain by Western blot analysis and normal subcellular distribution of torsinA in neurons by confocal microscopy. No animals had dystonic features. However, mice overexpressing hMT, but not hWT, torsinA displayed a reduced ability to learn motor skills in an accelerating rotarod paradigm. This pattern resembles the impaired motor sequence learning demonstrated in human nonmanifesting carriers of the DeltaGAG mutation. Open-field testing showed no differences in spontaneous activity between transgenic mice and their nontransgenic littermates, indicating that mice overexpressing hMT torsinA did not develop overtly abnormal motor behavior. Together, these data suggest that these transgenic mice provide a useful model of the DeltaGAG carrier state that can be used to probe genetic and environmental factors that can trigger the dystonic state.
Sharma
Nutan
N
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA. Nsharma@partners.org
Baxter
Mark G
MG
Petravicz
Jeremy
J
Bragg
D Cristopher
DC
Schienda
Alonna
A
Standaert
David G
DG
Breakefield
Xandra O
XO
D000818:Animals; D001921:Brain / Q000378:metabolism*; D004421:Dystonia / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007858:Learning; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D018832:Molecular Chaperones / Q000096:biosynthesis* / Q000235:genetics; D009043:Motor Activity; D009474:Neurons / Q000378:metabolism; D045442:Rotarod Performance Test
D018832:Molecular Chaperones; C108175:TOR1A protein, human