title: A role for cerebellum in the hereditary dystonia DYT1.
abstract: DYT1 is a debilitating movement disorder caused by loss-of-function mutations in torsinA. How these mutations cause dystonia remains unknown. Mouse models which have embryonically targeted torsinA have failed to recapitulate the dystonia seen in patients, possibly due to differential developmental compensation between rodents and humans. To address this issue, torsinA was acutely knocked down in select brain regions of adult mice using shRNAs. TorsinA knockdown in the cerebellum, but not in the basal ganglia, was sufficient to induce dystonia. In agreement with a potential developmental compensation for loss of torsinA in rodents, torsinA knockdown in the immature cerebellum failed to produce dystonia. Abnormal motor symptoms in knockdown animals were associated with irregular cerebellar output caused by changes in the intrinsic activity of both Purkinje cells and neurons of the deep cerebellar nuclei. These data identify the cerebellum as the main site of dysfunction in DYT1, and offer new therapeutic targets.
authors.affiliation: Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, New York, United States.
authors.forename: Rachel
authors.identifier: 0000-0001-5285-7899
authors.initials: R
authors.lastname: Fremont
authors.affiliation: Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, New York, United States.
authors.forename: Ambika
authors.identifier: 0000-0002-8740-5080
authors.initials: A
authors.lastname: Tewari
authors.affiliation: Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, New York, United States.
authors.forename: Chantal
authors.identifier: 0000-0002-2672-8249
authors.initials: C
authors.lastname: Angueyra
authors.affiliation: Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, New York, United States.
authors.forename: Kamran
authors.identifier: 0000-0001-7905-5335
authors.initials: K
authors.lastname: Khodakhah
mesh_terms: D000818:Animals; D002531:Cerebellum / Q000473:pathology*; D004195:Disease Models, Animal; D004422:Dystonia Musculorum Deformans / Q000235:genetics* / Q000473:pathology*; D055785:Gene Knockdown Techniques; D051379:Mice; D018832:Molecular Chaperones / Q000235:genetics*
chemical_list: C491548:Dyt1 protein, mouse; D018832:Molecular Chaperones
keywords: DYT1; basal ganglia; cerebellum; dystonia; mouse; neuroscience