Vanishing white matter: deregulated integrated stress response as therapy target
Rattachement africain : nl, us. Niveau de preuve : code pays fourni par la source.
Le résumé fourni par la source
OBJECTIVE: 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. METHODS: 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. RESULTS: In 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. INTERPRETATION: The present findings show that ISR deregulation is central in VWM pathomechanisms and a viable target for therapy.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Vanishing white matter: deregulated integrated stress response as therapy target
- Date Crossref
- 18/07/2019
- Éditeur
- Wiley
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Emma Kinderziekenhuis pays non établi dans la noticeÉtablissement de santé
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Amsterdam Neuroscience Department of Molecular and Cellular Neurobiology pays non établi dans la noticeStructure de recherche
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Amsterdam University Medical Centers Child Neurology Emma Children’s Hospital pays non établi dans la noticeÉtablissement de santé
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Cognitive Research (United States) pays non établi dans la noticeEntreprise
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Utrecht University Developmental Biology pays non établi dans la noticeUniversité ou école supérieure
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Vrije Universiteit Amsterdam pays non établi dans la noticeUniversité ou école supérieure
Emma Kinderziekenhuis, Department of Molecular and Cellular Neurobiology — Amsterdam Neuroscience et Child Neurology Emma Children’s Hospital — Amsterdam University Medical Centers, avec 3 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.