Chronic integrated stress response causes dysregulated cholesterol synthesis in white matter disease.

ABSTRACT: Maladaptive integrated stress response (ISR) activation is observed in human diseases of the brain. Genetic mutations of eIF2B, a critical mediator of protein synthesis, cause chronic pathway activation resulting in a leukodystrophy, but the precise mechanism is unknown. We generated N208Y eIF2B-α mice and found that this metabolite binding mutation led to destabilization of eIF2B-α, a systemic ISR, and neonatal lethality. 2BAct, an eIF2B activator, rescued lethality and significantly extended the lifespan of this severe model, underscoring its therapeutic potential in pediatric disease. Continuous treatment was required for survival, as withdrawal led to ISR induction in all tissues and rapid deterioration, thereby providing a model to assess the impact of the ISR in vivo by tuning drug a

SUBMITTER: Lin K 

PROVIDER: S-EPMC12406721 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature