Abstract

Vanishing White Matter disease (VWM) is a severe leukodystrophy of the central nervous system caused by mutations in subunits of the eukaryotic initiation factor 2B complex (eIF2B). Current models only partially recapitulate key disease features, and pathophysiology is poorly understood. Through development and validation of zebrafish (Danio rerio) models of VWM, we demonstrate that zebrafish eif2b mutants phenocopy VWM, including impaired somatic growth, early lethality, effects on myelination, loss of oligodendrocyte precursor cells, increased apoptosis in the CNS, and impaired motor swimming behavior. Expression of human EIF2B2 in the zebrafish eif2b2 mutant rescues lethality and CNS apoptosis, demonstrating conservation of function between zebrafish and human. In the mutants, intron 12 retention leads to expression of a truncated eif2b5 transcript. Expression of the truncated eif2b5 in wild-type larva impairs motor behavior and activates the ISR, suggesting that a feed-forward mechanism in VWM is a significant component of disease pathophysiology.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 1, 2, 3, 4, 5, and 6.

Article and author information

Author details

  1. Matthew D Keefe

    Pediatrics, University of Utah, Salt Lake City, United States
    Competing interests
    No competing interests declared.
  2. Haille E Soderholm

    Pediatrics, University of Utah, Salt Lake City, United States
    Competing interests
    No competing interests declared.
  3. Hung-Yu Shih

    Pediatrics, University of Utah, Salt Lake City, United States
    Competing interests
    No competing interests declared.
  4. Tamara J Stevenson

    Pediatrics, University of Utah, Salt Lake City, United States
    Competing interests
    No competing interests declared.
  5. Kathryn A Glaittli

    Pediatrics, University of Utah, Salt Lake City, United States
    Competing interests
    No competing interests declared.
  6. D Miranda Bowles

    Pediatrics, University of Utah, Salt Lake City, United States
    Competing interests
    No competing interests declared.
  7. Erika Scholl

    Pediatrics, University of Utah, Salt Lake City, United States
    Competing interests
    No competing interests declared.
  8. Samuel Colby

    Bioengineering, University of Utah, Salt Lake City, United States
    Competing interests
    No competing interests declared.
  9. Samer Merchant

    Bioengineering, University of Utah, Salt Lake City, United States
    Competing interests
    No competing interests declared.
  10. Edward W Hsu

    Bioengineering, University of Utah, Salt Lake City, United States
    Competing interests
    No competing interests declared.
  11. Joshua L Bonkowsky

    Pediatrics, University of Utah, Salt Lake City, United States
    For correspondence
    joshua.bonkowsky@hsc.utah.edu
    Competing interests
    Joshua L Bonkowsky, Consultant:Bluebird Bio (5/2017; 10/2017; 11/2019)Calico (1/2018-1/2019)Denali therapeutics (6/2019)Enzyvant (6/2019)Neurogene (3/2020)Board of Directorswfluidx 1/2018-presentStockOrchard Therapeutics.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8775-147X

Funding

National Institutes of Health (1R21 NS109441-01)

  • Joshua L Bonkowsky

University of Utah (Bray Chair)

  • Joshua L Bonkowsky

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

Reviewing Editor

  1. Beth Stevens, Boston Children's Hospital, United States

Ethics

Animal experimentation: Zebrafish experiments were performed in strict accordance of guidelines from the University of Utah Institutional Animal Care and Use Committee (IACUC), regulated under federal law (the Animal Welfare Act and Public Health Services Regulation Act) by the U.S. Department of Agriculture (USDA) and the Office of Laboratory Animal Welfare at the NIH, and accredited by the Association for Assessment and Accreditation of Laboratory Care International (AAALAC).

Human subjects: Human subjects-related aspects of the study were approved by the Institutional Review Board of the University of Utah and the Privacy Board of Intermountain Healthcare. Informed consent was obtained including consent to publish, protocol #19596.

Version history

  1. Received: February 24, 2020
  2. Accepted: December 9, 2020
  3. Accepted Manuscript published: December 10, 2020 (version 1)
  4. Version of Record published: December 21, 2020 (version 2)

Copyright

© 2020, Keefe 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. Matthew D Keefe
  2. Haille E Soderholm
  3. Hung-Yu Shih
  4. Tamara J Stevenson
  5. Kathryn A Glaittli
  6. D Miranda Bowles
  7. Erika Scholl
  8. Samuel Colby
  9. Samer Merchant
  10. Edward W Hsu
  11. Joshua L Bonkowsky
(2020)
Vanishing white matter disease expression of truncated EIF2B5 activates induced stress response
eLife 9:e56319.
https://doi.org/10.7554/eLife.56319

Share this article

https://doi.org/10.7554/eLife.56319

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