Impaired Eukaryotic Translation Initiation Factor 2B Activity Specifically in Oligodendrocytes Reproduces the Pathology of Vanishing White Matter Disease in Mice

Abstract

Vanishing white matter disease (VWMD) is an inherited autosomal-recessive hypomyelinating disease caused by mutations in eukaryotic translation initiation factor 2B (eIF2B). eIF2B mutations predominantly affect the brain white matter, and the characteristic features of VWMD pathology include myelin loss and foamy oligodendrocytes. Activation of pancreatic endoplasmic reticulum kinase (PERK) has been observed in oligodendrocytes in VWMD. PERK activation in response to endoplasmic reticulum stress attenuates eIF2B activity by phosphorylating eIF2␣, suggesting that impaired eIF2B activity in oligodendrocytes induced by VWMD mutations or PERK activation exploit similar mechanisms to promote selective white matter pathology in VWMD. Using transgenic mice that allow for temporally controlled activation of PERK specifically in oligodendrocytes, we discovered that strong PERK activation in oligodendrocytes during development suppressed eIF2B activity and reproduced the characteristic features of VWMD in mice, including hypomyelinating phenotype, foamy oligodendrocytes, and myelin loss. Notably, impaired eIF2B activity induced by PERK activation in oligodendrocytes of fully myelinated adult mice had minimal effects on morphology or function. Our observations point to a cell-autonomous role of impaired eIF2B activity in myelinating oligodendrocytes in the pathogenesis of VWMD.

Astrocytes are central in the pathomechanisms of vanishing white matter

“…PERK activation decreases eIF2B activity via phosphorylation of the initiation factor eIF2, while in VWM, eIF2B activity is affected by mutations in eIF2B subunit genes and not invariably decreased (9). Our results, especially the coculture data, contradict the conclusion of Lin et al (52).…”

“…This mutant mouse had a normal lifespan, subtle motor impairment at most, and white matter abnormalities that only became manifest after experimental demyelination (30,53). Using transgenic mice that allow activation of PERK specifically in oligodendrocytes, Lin et al (52) concluded that PERK activation in oligodendrocytes plays a cell-autonomous role in VWM pathology. PERK activation decreases eIF2B activity via phosphorylation of the initiation factor eIF2, while in VWM, eIF2B activity is affected by mutations in eIF2B subunit genes and not invariably decreased (9).…”

Molecular Determinants of the Regulation of Development and Metabolism by Neuronal eIF2α Phosphorylation in Caenorhabditis elegans

“…The enrichment of neuropathology-associated eIF2B mutant alleles suggests critical roles of eIF2B subunits in regulating homeostasis and myelin formation function of glial cells in the mammalian brain (Lin et al 2014). We also note that the eIF2B regulatory d-subunit has been identified as the molecular target of the drug ISRIB that renders mammalian neurons refractory to eIF2a phosphorylation to enhance memory formation (Sekine et al 2015;Sidrauski et al 2015).…”

Endoplasmic reticulum stress and the unfolded protein response in disorders of myelinating glia

“…Mouse models that reproduce the characteristics of VWMD have been difficult to produce (Lin et al, 2014b). Point mutations in eIF2B reproduce some white matter deficits but to a much milder degree than seen in VWMD.…”

“…Point mutations in eIF2B reproduce some white matter deficits but to a much milder degree than seen in VWMD. While the role that ER stress plays in the phenotype of these mouse models has not been examined (Geva et al, 2010), a recent study using transgenic mice provides evidence for a role of ER stress in VWMD (Lin et al, 2014b). PLP/Fv2E-PERK transgenic mice allow for oligodendrocyte-specific expression of a chimeric protein that contains the luminal eIF2α kinase domain of PERK fused to a small molecule-driven artificial dimerizing domain.…”