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Suppression of C9orf72 RNA repeat-induced neurotoxicity by the ALS-associated RNA-binding protein Zfp106

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Cite this article as: eLife 2017;6:e19032 doi: 10.7554/eLife.19032

Abstract

Expanded GGGGCC repeats in the first intron of the C9orf72 gene represent the most common cause of familial amyotrophic lateral sclerosis (ALS), but the mechanisms underlying repeat-induced disease remain incompletely resolved. One proposed gain-of-function mechanism is that repeat-containing RNA forms aggregates that sequester RNA binding proteins, leading to altered RNA metabolism in motor neurons. Here, we identify the zinc finger protein Zfp106 as a specific GGGGCC RNA repeat-binding protein, and using affinity purification-mass spectrometry, we show that Zfp106 interacts with multiple other RNA binding proteins, including the ALS-associated factors TDP-43 and FUS. We also show that Zfp106 knockout mice develop severe motor neuron degeneration, which can be suppressed by transgenic restoration of Zfp106 specifically in motor neurons. Finally, we show that Zfp106 potently suppresses neurotoxicity in a Drosophila model of C9orf72 ALS. Thus, these studies identify Zfp106 as an RNA binding protein with important implications for ALS.

Article and author information

Author details

  1. Barbara Celona

    Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. John von Dollen

    Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Sarat C Vatsavayai

    Department of Neurology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Risa Kashima

    Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Jeffrey R Johnson

    Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Amy A Tang

    Department of Pathology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Akiko Hata

    Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Bruce L Miller

    Department of Neurology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Eric J Huang

    Department of Pathology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Nevan J Krogan

    Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. William W Seeley

    Department of Neurology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Brian L Black

    Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States
    For correspondence
    brian.black@ucsf.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6664-8913

Funding

American Heart Association (14POST1862005)

  • Barbara Celona

Sandler Foundation

  • Barbara Celona

National Institutes of Health (HL064658)

  • Brian L Black

National Institutes of Health (HL089707)

  • Brian L Black

Amyotrophic Lateral Sclerosis Association (17-IIP-358)

  • Brian L Black

National Institutes of Health (P01AG019724)

  • Bruce L Miller
  • William W Seeley

National Institutes of Health (P50AG023501)

  • Bruce L Miller
  • William W Seeley

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 using vertebrate animals were reviewed and approved by the University of California, San Francisco Institutional Animal Care and Use Committee (IACUC) under protocols AN108111 and AN087046, and all animal research complied with all institutional and federal guidelines.

Reviewing Editor

  1. Didier YR Stainier, Max Planck Institute for Heart and Lung Research, Germany

Publication history

  1. Received: June 22, 2016
  2. Accepted: January 2, 2017
  3. Accepted Manuscript published: January 10, 2017 (version 1)
  4. Version of Record published: January 31, 2017 (version 2)

Copyright

© 2017, Celona 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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