Forebrain deletion of the dystonia protein torsinA causes dystonic-like movements and loss of striatal cholinergic neurons
Samuel S Pappas,
Katherine Darr,
Sandra M Holley,
Carlos Cepeda,
Omar S Mabrouk,
Jenny-Marie T Wong,
Tessa M LeWitt,
Reema Paudel,
Henry Houlden,
Robert T Kennedy,
Michael S Levine,
William T Dauer
Affiliations
Samuel S Pappas
Department of Neurology, University of Michigan, Ann Arbor, United States
Katherine Darr
Department of Neurology, University of Michigan, Ann Arbor, United States
Sandra M Holley
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
Carlos Cepeda
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
Omar S Mabrouk
Department of Pharmacology, University of Michigan, Ann Arbor, United States
Jenny-Marie T Wong
Department of Chemistry, University of Michigan, Ann Arbor, United States
Tessa M LeWitt
Department of Neurology, University of Michigan, Ann Arbor, United States
Reema Paudel
Department of Molecular Neuroscience, Institute of Neurology, University College London, London, United Kingdom
Henry Houlden
Department of Molecular Neuroscience, Institute of Neurology, University College London, London, United Kingdom
Robert T Kennedy
Department of Chemistry, University of Michigan, Ann Arbor, United States
Michael S Levine
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
William T Dauer
Department of Neurology, University of Michigan, Ann Arbor, United States; Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, United States
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.
