Integrated Stress Response Deregulation underlies Vanishing White Matter and is a target for therapy

BioRxiv : the Preprint Server for Biology
T E M AbbinkM S van der Knaap

Abstract

Vanishing white matter (VWM) is a fatal, stress-sensitive leukodystrophy that mainly affects children and is currently without treatment. VWM is caused by recessive mutations in eukaryotic initiation factor 2B (eIF2B) that is crucial for initiation of mRNA translation and its regulation under stress conditions. Mice with bi-allelic missense mutations in eIF2B recapitulate human VWM. VWM pathomechanisms are unclear. Using polysomal profiling to screen for mRNAs with altered translation we observed most prominent changes in expression of integrated stress response (ISR) mRNAs in brains of mutant compared to wild-type mice; expression levels correlated with disease severity. We substantiated these findings in VWM patients' brains. ISRIB, an ISR inhibitor, normalized expression of mRNA markers, ameliorated white matter pathology and improved motor skills in VWM mice, thus showing that the ISR is central in VWM pathomechanisms and a viable target for therapy.

Related Concepts

Biological Markers
Brain
Leukodystrophy
Laboratory mice
Pathology
RNA, Messenger
Biological Adaptation to Stress
Inhibitors
Plant material (substance)
Mutant

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