1. Cell Biology
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A novel ALS-associated variant in UBQLN4 regulates motor axon morphogenesis

  1. Brittany M Edens
  2. Jianhua Yan
  3. Han-Xiang Deng
  4. Teepu Siddique
  5. Yongchao Charles Ma  Is a corresponding author
  1. Northwestern University Feinberg School of Medicine, United States
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Cite this article as: eLife 2017;6:e25453 doi: 10.7554/eLife.25453

Abstract

The etiological underpinnings of amyotrophic lateral sclerosis (ALS) are complex and incompletely understood, although contributions to pathogenesis by regulators of proteolytic pathways have become increasingly apparent. Here, we present a novel variant in UBQLN4 that is associated with ALS and show that its expression compromises motor axon morphogenesis in mouse motor neurons and in zebrafish. We further demonstrate that the ALS-associated UBQLN4 variant impairs proteasomal function, and identify the Wnt signaling pathway effector beta-catenin as a UBQLN4 substrate. Inhibition of beta-catenin function rescues the UBQLN4 variant-induced motor axon phenotypes. These findings provide a strong link between the regulation of axonal morphogenesis and a new ALS-associated gene variant mediated by protein degradation pathways.

Article and author information

Author details

  1. Brittany M Edens

    Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Jianhua Yan

    Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Han-Xiang Deng

    Division of Neuromuscular Medicine, Davee Department of Neurology and Clinical Neurosciences, Northwestern University Feinberg School of Medicine, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Teepu Siddique

    Division of Neuromuscular Medicine, Davee Department of Neurology and Clinical Neurosciences, Northwestern University Feinberg School of Medicine, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Yongchao Charles Ma

    Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, United States
    For correspondence
    ma@northwestern.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2469-4356

Funding

National Institute of Neurological Disorders and Stroke (NS094564)

  • Yongchao Charles Ma

National Institute on Aging (AG043970)

  • Yongchao Charles Ma

Hartwell Foundation

  • Yongchao Charles Ma

Whitehall Foundation

  • Yongchao Charles Ma

National Institute of Neurological Disorders and Stroke (NS078504)

  • Teepu Siddique

Les Turner ALS Foundation

  • Teepu Siddique

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 animal use in this study has been approved by the Institutional Animal Care and Use Committee (IACUC) of the Lurie Children's Hospital of Chicago (protocols 14-012 and 15-006). All studies were conducted in accordance with the US Public Health Service's Policy on Humane Care and Use of Laboratory Animals.

Human subjects: The use of human subjects in this study has been approved by the Northwestern University Institutional Review Board (IRB). Informed consent was obtained from all subjects.

Reviewing Editor

  1. Anne E West, Duke University School of Medicine, United States

Publication history

  1. Received: January 25, 2017
  2. Accepted: April 29, 2017
  3. Accepted Manuscript published: May 2, 2017 (version 1)
  4. Accepted Manuscript updated: May 4, 2017 (version 2)
  5. Version of Record published: May 31, 2017 (version 3)

Copyright

© 2017, Edens 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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