Forebrain deletion of the dystonia protein torsinA causes dystonic-like movements and loss of striatal cholinergic neurons

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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.

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Samuel S Pappas

Department of Neurology, University of Michigan, Ann Arbor, United States

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The authors declare that no competing interests exist.
Katherine Darr

Department of Neurology, University of Michigan, Ann Arbor, United States

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The authors declare that no competing interests exist.
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

Competing interests
The authors declare that no competing interests exist.
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

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The authors declare that no competing interests exist.
Omar S Mabrouk

Department of Pharmacology, University of Michigan, Ann Arbor, United States

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The authors declare that no competing interests exist.
Jenny-Marie T Wong

Department of Chemistry, University of Michigan, Ann Arbor, United States

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The authors declare that no competing interests exist.
Tessa M LeWitt

Department of Neurology, University of Michigan, Ann Arbor, United States

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The authors declare that no competing interests exist.
Reema Paudel

Department of Molecular Neuroscience, Institute of Neurology, University College London, London, United Kingdom

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The authors declare that no competing interests exist.
Henry Houlden

Department of Molecular Neuroscience, Institute of Neurology, University College London, London, United Kingdom

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The authors declare that no competing interests exist.
Robert T Kennedy

Department of Chemistry, University of Michigan, Ann Arbor, United States

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The authors declare that no competing interests exist.
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

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The authors declare that no competing interests exist.
William T Dauer

Department of Neurology, University of Michigan, Ann Arbor, United States

For correspondence
dauer@med.umich.edu

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The authors declare that no competing interests exist.

Ethics

Animal experimentation: All experiments were performed according to the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. The University of Michigan Committee on the Use and Care of Animals (UCUCA) approved all experiments involving animals (animal use protocol PRO00004330).

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.