Vanishing white matter disease expression of truncated EIF2B5 activates induced stress response.

Autor:	Keefe MD; Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, United States., Soderholm HE; Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, United States., Shih HY; Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, United States., Stevenson TJ; Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, United States., Glaittli KA; Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, United States., Bowles DM; Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, United States., Scholl E; Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, United States., Colby S; Department of Bioengineering, University of Utah, Salt Lake City, United States., Merchant S; Department of Bioengineering, University of Utah, Salt Lake City, United States., Hsu EW; Department of Bioengineering, University of Utah, Salt Lake City, United States., Bonkowsky JL; Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, United States.; Brain and Spine Center, Primary Children's Hospital, Salt Lake City, United States.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2020 Dec 10; Vol. 9. Date of Electronic Publication: 2020 Dec 10.
DOI:	10.7554/eLife.56319
Abstrakt:	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. Competing Interests: MK, HS, HS, TS, KG, DB, ES, SC, SM, EH No competing interests declared, JB 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 Directors wfluidx 1/2018-present Stock Orchard Therapeutics (© 2020, Keefe et al.)
Databáze:	MEDLINE
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