Vanishing white matter: deregulated integrated stress response as therapy target

Annals of Clinical and Translational Neurology
Truus E M AbbinkMarjo 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 during the integrated stress response (ISR). Mutations reduce eIF2B activity. VWM pathomechanisms remain unclear. In contrast with the housekeeping function of eIF2B, astrocytes are selectively affected in VWM. One study objective was to test our hypothesis that in the brain translation of specific mRNAs is altered by eIF2B mutations, impacting primarily astrocytes. The second objective was to investigate whether modulation of eIF2B activity could ameliorate this altered translation and improve the disease. Mice with biallelic missense mutations in eIF2B that recapitulate human VWM were used to screen for mRNAs with altered translation in brain using polysomal profiling. Findings were verified in brain tissue from VWM patients using qPCR and immunohistochemistry. The compound ISRIB (for "ISR inhibitor") was administered to VWM mice to increase eIF2B activity. Its effect on translation, neuropathology, and clinical signs was assessed. In brains o...Continue Reading

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Citations

Aug 15, 2020·Frontiers in Molecular Biosciences·Anne E J Hillen, Vivi M Heine
Jan 13, 2021·Molecular Genetics & Genomic Medicine·Inna SlynkoMarjo S van der Knaap
Mar 24, 2020·Biochemistry·Assen Marintchev, Takuhiro Ito
Oct 8, 2020·Brain Research Bulletin·Konstantin N ZabegalovAllan V Kalueff
Apr 4, 2021·International Journal of Molecular Sciences·Doeun KimSangkyu Lee
Jun 30, 2021·Radiology·Menno D StellingwerffMarjo S van der Knaap
Aug 8, 2021·International Journal of Molecular Sciences·Garrett Dalton SmedleyShauna H Yuan
Aug 28, 2021·International Journal of Molecular Sciences·Hiroto YasudaHideaki Hara
Sep 1, 2021·Wiley Interdisciplinary Reviews. RNA·Alyssa M EnglishStephanie L Moon

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Methods Mentioned

BETA
transfection

Software Mentioned

ISRIB
CatWalk
SPSS

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