title: Forebrain deletion of the dystonia protein torsinA causes dystonic-like movements and loss of striatal cholinergic neurons.
abstract: Striatal dysfunction plays an important role in dystonia, but the striatal cell types that contribute to abnormal movements are poorly defined. We demonstrate that conditional deletion of the DYT1 dystonia protein torsinA in embryonic progenitors of forebrain cholinergic and GABAergic neurons causes dystonic-like twisting movements that emerge during juvenile CNS maturation. The onset of these movements coincides with selective degeneration of dorsal striatal large cholinergic interneurons (LCI), and surviving LCI exhibit morphological, electrophysiological, and connectivity abnormalities. Consistent with the importance of this LCI pathology, murine dystonic-like movements are reduced significantly with an antimuscarinic agent used clinically, and we identify cholinergic abnormalities in postmortem striatal tissue from DYT1 dystonia patients. These findings demonstrate that dorsal LCI have a unique requirement for torsinA function during striatal maturation, and link abnormalities of these cells to dystonic-like movements in an overtly symptomatic animal model.
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, United States.
authors.forename: Samuel S
authors.initials: SS
authors.lastname: Pappas
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, United States.
authors.forename: Katherine
authors.initials: K
authors.lastname: Darr
authors.affiliation: Intellectual and Developmental Disabilities Research Center, Brain Research Institute, Semel Institute for Neuroscience, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States.
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Holley
authors.affiliation: Intellectual and Developmental Disabilities Research Center, Brain Research Institute, Semel Institute for Neuroscience, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States.
authors.forename: Carlos
authors.initials: C
authors.lastname: Cepeda
authors.affiliation: Department of Pharmacology, University of Michigan, Ann Arbor, United States.
authors.forename: Omar S
authors.initials: OS
authors.lastname: Mabrouk
authors.affiliation: Department of Chemistry, University of Michigan, Ann Arbor, United States.
authors.forename: Jenny-Marie T
authors.initials: JM
authors.lastname: Wong
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, United States.
authors.forename: Tessa M
authors.initials: TM
authors.lastname: LeWitt
authors.affiliation: Department of Molecular Neuroscience, Institute of Neurology, University College London, London, United Kingdom.
authors.forename: Reema
authors.initials: R
authors.lastname: Paudel
authors.affiliation: Department of Molecular Neuroscience, Institute of Neurology, University College London, London, United Kingdom.
authors.forename: Henry
authors.initials: H
authors.lastname: Houlden
authors.affiliation: Department of Chemistry, University of Michigan, Ann Arbor, United States.
authors.forename: Robert T
authors.initials: RT
authors.lastname: Kennedy
authors.affiliation: Intellectual and Developmental Disabilities Research Center, Brain Research Institute, Semel Institute for Neuroscience, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Levine
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, United States.
authors.forename: William T
authors.initials: WT
authors.lastname: Dauer
mesh_terms: D000818:Animals; D059329:Cholinergic Neurons / Q000473:pathology*; D003342:Corpus Striatum / Q000473:pathology*; D004421:Dystonia / Q000473:pathology*; D017353:Gene Deletion; D051379:Mice; D018832:Molecular Chaperones / Q000235:genetics*; D009068:Movement; D016548:Prosencephalon / Q000196:embryology*
chemical_list: C491548:Dyt1 protein, mouse; D018832:Molecular Chaperones
keywords: cholinergic interneurons; dystonia; mouse; neurodegeneration; neurogenetics; neuroscience; striatum; torsinA