ArticleeLife2018
The small molecule ISRIB rescues the stability and activity of Vanishing White Matter Disease eIF2B mutant complexes.
Article in eLife, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 76 papers.
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Who cites it
76 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
- Review
- Progenitor Resilience and the Early Onset of Chronic Lung Diseases: NHLBI workshop report.American journal of respiratory cell and molecular biology · 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
- Overcoming immunotherapy resistance in breast cancer: a novel strategy by targeting the integrated stress response.Frontiers in cell and developmental biology · 2026Review
- Prime editing links the split integrated stress response to pathogenic eIF2B mutations and white matter degeneration.Cell death & disease · 2025Article
- A scoping review of stem cell models of leukodystrophies: advances in understanding pathophysiological mechanisms.NPJ genomic medicine · 2025Article
- Importance of De Novo Gene Evolution to Emerging Viral Threats: The ORF10 Strain-Restricted Orphan Gene of SARS-CoV-2 Promotes Pathogenesis.Molecular biology and evolution · 2025Article
- Chronic integrated stress response causes dysregulated cholesterol synthesis in white matter disease.JCI insight · 2025Article
- Dual Nature of Mitochondrial Integrated Stress Response: Molecular Switches from Protection to Pathology.Genes · 2025Review
- Eukaryotic translation initiation factor 2A protects pancreatic beta cells during endoplasmic reticulum stress while rescuing global translation inhibition.Diabetologia · 2025Article
- EIF2A mediates beta cell resilience during endoplasmic reticulum stress: mechanistic insights and therapeutic opportunities.Diabetologia · 2025Article
- The Link Between Endoplasmic Reticulum Stress and Lysosomal Dysfunction Under Oxidative Stress in Cancer Cells.Biomolecules · 2025Review
- Homeostasis control in health and disease by the unfolded protein response.Nature reviews. Molecular cell biology · 2025Review
- CRISPuRe-seq: pooled screening of barcoded ribonucleoprotein reporters reveals regulation of RNA polymerase III transcription by the integrated stress response via mTOR.Nucleic acids research · 2025Article
- Case Report: New genetic variant and widely different phenotypes observed in twins with Vanishing White Matter disease.Frontiers in pediatrics · 2025Article
- Maximizing ISRIB Potential Requires Addressing Specificity, Long-term Safety, and Disease-specific Considerations.Current medicinal chemistry · 2025Review
- Evaluation of safety and early efficacy of AAV gene therapy in mouse models of vanishing white matter disease.Molecular therapy : the journal of the American Society of Gene Therapy · 2024Article
16 more citing papers are in PubMed but not listed here.
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
eIF2B is a dedicated guanine nucleotide exchange factor for eIF2, the GTPase that is essential to initiate mRNA translation. The integrated stress response (ISR) signaling pathway inhibits eIF2B activity, attenuates global protein synthesis and upregulates a set of stress-response proteins. Partial loss-of-function mutations in eIF2B cause a neurodegenerative disorder called Vanishing White Matter Disease (VWMD). Previously, we showed that the small molecule ISRIB is a specific activator of eIF2B (<xref ref-type="bibr" rid="bib38">Sidrauski et al., 2015</xref>). Here, we report that various VWMD mutations destabilize the decameric eIF2B holoenzyme and impair its enzymatic activity. ISRIB stabilizes VWMD mutant eIF2B in the decameric form and restores the residual catalytic activity to wild-type levels. Moreover, ISRIB blocks activation of the ISR in cells carrying these mutations. As such, ISRIB promises to be an invaluable tool in proof-of-concept studies aiming to ameliorate defects resulting from inappropriate or pathological activation of the ISR.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.