Vanishing white matter disease expression of truncated EIF2B5 activates induced stress response
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.
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
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.
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.
- Beth Stevens, Boston Children's Hospital, United States
- Received: February 24, 2020
- Accepted: December 9, 2020
- Accepted Manuscript published: December 10, 2020 (version 1)
- Version of Record published: December 21, 2020 (version 2)
© 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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