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Nemo-like kinase is a novel regulator of spinal and bulbar muscular atrophy

  1. Tiffany W Todd
  2. Hiroshi Kokubu
  3. Helen C Miranda
  4. Constanza J Cortes
  5. Albert R La Spada
  6. Janghoo Lim  Is a corresponding author
  1. Yale School of Medicine, United States
  2. University of California, San Diego, United States
Research Article
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Cite this article as: eLife 2015;4:e08493 doi: 10.7554/eLife.08493

Abstract

Spinal and Bulbar Muscular Atrophy (SBMA) is a progressive neuromuscular disease caused by polyglutamine expansion in the Androgen Receptor (AR) protein. Despite extensive research, the exact pathogenic mechanisms underlying SBMA remain elusive. Here we present evidence that Nemo-Like Kinase (NLK) promotes disease pathogenesis across multiple SBMA model systems. Most remarkably, loss of one copy of Nlk rescues SBMA phenotypes in mice, including extending lifespan. We also investigated the molecular mechanisms by which NLK exerts its effects in SBMA. Specifically, we have found that NLK can phosphorylate the mutant polyglutamine-expanded AR, enhance its aggregation, and promote AR-dependent gene transcription by regulating AR-cofactor interactions. Furthermore, NLK modulates the toxicity of a mutant AR fragment via a mechanism that is independent of AR-mediated gene transcription. Our findings uncover a crucial role for NLK in controlling SBMA toxicity and reveal a novel avenue for therapy development in SBMA.

Article and author information

Author details

  1. Tiffany W Todd

    Program in Cellular Neuroscience, Neurodegeneration and Repair, Department of Genetics, Yale School of Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Hiroshi Kokubu

    Program in Cellular Neuroscience, Neurodegeneration and Repair, Department of Genetics, Yale School of Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Helen C Miranda

    Departments of Cellular and Molecular Medicine, Neurosciences and Pediatrics, Division of Biological Sciences, Institute for Genomic Medicine, Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Constanza J Cortes

    Departments of Cellular and Molecular Medicine, Neurosciences and Pediatrics, Division of Biological Sciences, Institute for Genomic Medicine, Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Albert R La Spada

    Departments of Cellular and Molecular Medicine, Neurosciences and Pediatrics, Division of Biological Sciences, Institute for Genomic Medicine, Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Janghoo Lim

    Program in Cellular Neuroscience, Neurodegeneration and Repair, Department of Genetics, Yale School of Medicine, New Haven, United States
    For correspondence
    janghoo.lim@yale.edu
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#2013-11342) of the Yale University. The Yale University Institutional Animal Care and Use Committee approved all research and animal care procedures. We made every effort to minimize animal suffering.

Reviewing Editor

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

Publication history

  1. Received: May 2, 2015
  2. Accepted: August 24, 2015
  3. Accepted Manuscript published: August 26, 2015 (version 1)
  4. Version of Record published: September 22, 2015 (version 2)

Copyright

© 2015, Todd 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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