eIF2B Activator Rescues Neonatal Lethality of an eIF2Bα Sugar Phosphate Binding Mutation Associated with Vanishing White Matter Disease

eIF2B is a decameric guanine nucleotide exchange factor (GEF) that is essential for protein synthesis and a key effector of the integrated stress response (ISR). Hypomorphic mutations in any of the eIF2B subunits are associated with Vanishing White Matter Disease (VWM), a leukodystrophy characterized by ISR activation and white matter loss. Here, we showed that the VWM-associated N208Y eIF2Bα mutation, which abolishes sugar phosphate binding, led to a drastic reduction in its level in cells and concomitant ISR activation. We found that N208Y homozygous mice are small and die shortly after birth. Remarkably, continuous availability of 2BAct, a small molecule eIF2B activator, in food rescued the lethality and significantly extended their lifespan. 2BAct-maintained N208Y homozygous mice, however, developed motor deficits and loss of myelin with age. As is the case for milder VWM models, ISR induction was restricted to the central nervous system in treated animals. Upon 2BAct withdrawal, adult mutant mice deteriorated quickly, the ISR was induced in all peripheral tissues tested and resulted in high levels of circulating FGF21 and GDF15. This model provides a novel platform to study the impact of ISR activation across tissues with temporal control.