1. Neuroscience

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

  1. Samuel S Pappas
  2. Katherine Darr
  3. Sandra M Holley
  4. Carlos Cepeda
  5. Omar S Mabrouk
  6. Jenny-Marie T Wong
  7. Tessa M LeWitt
  8. Reema Paudel
  9. Henry Houlden
  10. Robert T Kennedy
  11. Michael S Levine
  12. William T Dauer  Is a corresponding author
  1. University of Michigan, United States
  2. University of California, Los Angeles, United States
  3. University College London, United Kingdom
https://doi.org/10.7554/eLife.08352
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Cite this article
  1. Samuel S Pappas
  2. Katherine Darr
  3. Sandra M Holley
  4. Carlos Cepeda
  5. Omar S Mabrouk
  6. Jenny-Marie T Wong
  7. Tessa M LeWitt
  8. Reema Paudel
  9. Henry Houlden
  10. Robert T Kennedy
  11. Michael S Levine
  12. William T Dauer
(2015)
Forebrain deletion of the dystonia protein torsinA causes dystonic-like movements and loss of striatal cholinergic neurons
eLife 4:e08352.
https://doi.org/10.7554/eLife.08352
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  3. Download .RIS

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.

Article and author information

Author details

  1. Samuel S Pappas

    Department of Neurology, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Katherine Darr

    Department of Neurology, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. 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.

  4. 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
    Competing interests
    The authors declare that no competing interests exist.

  5. Omar S Mabrouk

    Department of Pharmacology, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.

  6. Jenny-Marie T Wong

    Department of Chemistry, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.

  7. Tessa M LeWitt

    Department of Neurology, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.

  8. Reema Paudel

    Department of Molecular Neuroscience, Institute of Neurology, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  9. Henry Houlden

    Department of Molecular Neuroscience, Institute of Neurology, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  10. Robert T Kennedy

    Department of Chemistry, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.

  11. 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
    Competing interests
    The authors declare that no competing interests exist.

  12. William T Dauer

    Department of Neurology, University of Michigan, Ann Arbor, United States
    For correspondence
    dauer@med.umich.edu
    Competing interests
    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).

Copyright

© 2015, Pappas et al.

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.

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  1. Samuel S Pappas
  2. Katherine Darr
  3. Sandra M Holley
  4. Carlos Cepeda
  5. Omar S Mabrouk
  6. Jenny-Marie T Wong
  7. Tessa M LeWitt
  8. Reema Paudel
  9. Henry Houlden
  10. Robert T Kennedy
  11. Michael S Levine
  12. William T Dauer
(2015)
Forebrain deletion of the dystonia protein torsinA causes dystonic-like movements and loss of striatal cholinergic neurons
eLife 4:e08352.
https://doi.org/10.7554/eLife.08352

Share this article

https://doi.org/10.7554/eLife.08352

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Further reading

    1. Neuroscience

    A cell autonomous torsinA requirement for cholinergic neuron survival and motor control

    Samuel S Pappas, Jay Li ... William T Dauer
    Research Advance Updated

    Cholinergic dysfunction is strongly implicated in dystonia pathophysiology. Previously (Pappas et al., 2015;4:e08352), we reported that Dlx5/6-Cre mediated forebrain deletion of the DYT1 dystonia protein torsinA (Dlx-CKO) causes abnormal twisting and selective degeneration of dorsal striatal cholinergic interneurons (ChI) (Pappas et al., 2015). A central question raised by that work is whether the ChI loss is cell autonomous or requires torsinA loss from neurons synaptically connected to ChIs. Here, we addressed this question by using ChAT-Cre mice to conditionally delete torsinA from cholinergic neurons (‘ChAT-CKO’). ChAT-CKO mice phenocopy the Dlx-CKO phenotype of selective dorsal striatal ChI loss and identify an essential requirement for torsinA in brainstem and spinal cholinergic neurons. ChAT-CKO mice are tremulous, weak, and exhibit trunk twisting and postural abnormalities. These findings are the first to demonstrate a cell autonomous requirement for torsinA in specific populations of cholinergic neurons, strengthening the connection between torsinA, cholinergic dysfunction and dystonia pathophysiology.

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