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

  1. Samuel S Pappas
  2. Jay Li
  3. Tessa M LeWitt
  4. Jeong-Ki Kim
  5. Umrao R Monani
  6. William T Dauer  Is a corresponding author
  1. University of Michigan, United States
  2. Columbia University, United States
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Cite this article as: eLife 2018;7:e36691 doi: 10.7554/eLife.36691

Abstract

Cholinergic dysfunction is strongly implicated in dystonia pathophysiology. Previously (Pappas et al., eLife 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) (1). 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.

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.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6980-2058
  2. Jay Li

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

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

    Department of Pathology, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Umrao R Monani

    Department of Pathology, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. 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.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1775-7504

Funding

National Institute of Neurological Disorders and Stroke (RO1NS077730)

  • William T Dauer

Tyler's Hope for a Dystonia Cure

  • William T Dauer

National Institutes of Health (RO1NS057482)

  • Umrao R Monani

National Institutes of Health (R21NS099921)

  • Umrao R Monani

National Institutes of Health (R56NS104218)

  • Umrao R Monani

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

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. All procedures involving animals were approved by the University of Michigan Institutional Animal Care and Use Committee (animal use protocol PRO00006600). All effort was taken to minimize the number of animals used and to prevent discomfort or distress.

Reviewing Editor

  1. Louis J Ptáček, University of California, San Francisco, United States

Publication history

  1. Received: March 15, 2018
  2. Accepted: August 16, 2018
  3. Accepted Manuscript published: August 17, 2018 (version 1)
  4. Version of Record published: August 29, 2018 (version 2)

Copyright

© 2018, 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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