ArticleAnnals of clinical and translational neurology2019
Vanishing white matter: deregulated integrated stress response as therapy target.
Article in Annals of clinical and translational neurology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 65 papers.
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Who cites it
65 citing papers in PubMed, 134 citations in OpenAlex.
- Investigational eIF2B activator DNL343 modulates the integrated stress response in preclinical models of TDP-43 pathology and individuals with ALS in a randomized clinical trial.Nature communications · 2025Trial
- White matter disorders at the intersection of transcription, RNA processing and translation.Nature reviews. Neurology · 2026Review
- Pediatric pharmacokinetics and pharmacodynamics of guanabenz for the treatment of vanishing white matter.Scientific reports · 2026Article
- Genomic insights into the tunicamycin-induced endoplasmic reticulum stress response in peripheral blood mononuclear cells: A comprehensive RNA sequencing analysis.Biochemistry and biophysics reports · 2026Article
- The Janus framework of the integrated stress response: from homeostasis to maladaptation.Life science alliance · 2026Review
- Endogenous Repair in Vanishing White Matter.Annals of neurology · 2026Article
- Regulation of Translation of ATF4 mRNA: A Focus on Translation Initiation Factors and RNA-Binding Proteins.Cells · 2026Review
- Directional Modulation of the Integrated Stress Response in Neurodegeneration: A Systematic Review of eIF2B Activators, PERK-Pathway Agents, and ISR Prolongers.Biomedicines · 2026Review
- Adult-onset vanishing white matter disease caused by the EIF2B5 c.185A>T (p.Asp62Val) variant.Frontiers in genetics · 2026Review
- Prime editing links the split integrated stress response to pathogenic eIF2B mutations and white matter degeneration.Cell death & disease · 2025Article
- Consensus-Based Expert Recommendations for Diagnosis and Clinical Management of Vanishing White Matter.Neurology · 2025Review
- Inhibition of integrated stress response by ISRIB promotes mouse and human primordial follicle activation via the mTOR pathway.Journal of assisted reproduction and genetics · 2025Article
- A scoping review of stem cell models of leukodystrophies: advances in understanding pathophysiological mechanisms.NPJ genomic medicine · 2025Article
- DDX3X acts as a selective dual switch regulator of mRNA translation in acute ER stress.Cell reports · 2025Article
- Cell-specific Eif2b5 mutant mice: novel insights into roles of macroglia in vanishing white matter.Brain : a journal of neurology · 2025Article
- The impact of vanishing white matter on unaffected family members.Orphanet journal of rare diseases · 2025Article
- Chronic integrated stress response causes dysregulated cholesterol synthesis in white matter disease.JCI insight · 2025Article
- Article
- Quantitative MRI distinguishes different leukodystrophies and correlates with clinical measures.European radiology · 2025Article
- The translational landscape of reactive astrocytes reveals the impact of eIF2B-mediated dysregulation in VWM disease.NAR molecular medicine · 2025Article
5 more citing papers are in PubMed but not listed here.
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Authors and funding
18 authors at 6 institutions in 2 countries.
Funding
Abstract
objectiveVanishing 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.
methodsMice 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.
resultsIn brains of VWM compared to wild-type mice we observed the most prominent changes in translation concerning ISR mRNAs; their expression levels correlated with disease severity. We substantiated these findings in VWM patients' brains. ISRIB normalized expression of mRNA markers, ameliorated brain white matter pathology and improved motor skills in VWM mice.
interpretationThe present findings show that ISR deregulation is central in VWM pathomechanisms and a viable target for therapy.
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