ArticleNature communications2025
Integrated stress response inhibition prolongs the lifespan of a Pelizaeus-Merzbacher disease mouse model by increasing oligodendrocyte survival.
Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed.
- White matter disorders at the intersection of transcription, RNA processing and translation.Nature reviews. Neurology · 2026Review
- Review
- Region Specific miRNA-mRNA Networks in Gray and White Matter Lesions of Progressive Multiple Sclerosis.Annals of clinical and translational neurology · 2026Article
- Review
- Distinct cell type-specific mechanisms underlie cognitive dysfunction during persistent integrated stress response activation.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- MDA5 and the integrated stress response control sex-specific type 1 diabetes onset in NOD mice.bioRxiv : the preprint server for biology · 2026Article
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Authors and funding
16 authors.
Funding
Abstract
The leukodystrophy Pelizaeus-Merzbacher disease (PMD) is caused by myelin protein proteolipid protein gene (PLP1) mutations. PMD is characterized by oligodendrocyte death and CNS hypomyelination; thus, increasing oligodendrocyte survival and enhancing myelination could provide therapeutic benefit. Here, we use the PMD mouse model Jimpy to determine the impact of the integrated stress response (ISR) on the oligodendrocyte response to mutant PLP expression. Male Jimpy animals in which the ISR-triggering eukaryotic initiation factor (eIF) 2α kinase, protein kinase-like endoplasmic reticulum kinase (PERK), is inactivated have an extended lifespan that correlates with increased oligodendrocyte survival and enhanced CNS myelination. Inactivation of downstream components of the ISR pathway, in contrast, does not rescue oligodendrocytes or myelin. Phosphorylated eIF2α inhibits the exchange factor eIF2B, resulting in diminished protein synthesis. Treatment with small molecule eIF2B activators 2BAct and ISRIB increases oligodendrocyte survival, CNS myelination, and doubled the Jimpy lifespan. These results suggest that ISR modulation could provide therapeutic benefit to PMD patients.
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