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

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 (<i>Danio rerio</i>) models of VWM, we demonstrate that zebrafish <i>eif2b</i> 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 <i>EIF2B2</i> in the zebrafish <i>eif2b2</i> 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 <i>eif2b5</i> transcript. Expression of the truncated <i>eif2b5</i> 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.