Endoplasmic reticulum stress modulates the response of myelinating oligodendrocytes to the immune cytokine interferon-γ

Interferon-gamma ( IFN-gamma) is believed to contribute to immune-mediated demyelinating disorders by targeting the myelinproducing oligodendrocyte, a cell known to be highly sensitive to the disruption of protein synthesis and to the perturbation of the secretory pathway. We found that apoptosis induced by IFN-gamma in cultured rat oligoden-drocytes was associated with endoplasmic reticulum ( ER) stress. ER stress also accompanied oligodendrocyte apoptosis and hypomyelination in transgenic mice that inappropriately expressed IFN-gamma in the central nervous system (CNS). Compared with a wild- type genetic background, the enforced expression of IFN-gamma in mice that were heterozygous for a loss of function mutation in pancreatic ER kinase ( PERK) dramatically reduced animal survival, promoted CNS hypomyelination, and enhanced oligodendrocyte loss. PERK encodes an ER stress - inducible kinase that phosphorylates eukaryotic translation initiation factor 2 alpha and specifically maintains client protein homeostasis in the stressed ER. Therefore, the hypersensitivity of PERK+/- mice to IFN-gamma implicates ER stress in demyelinating disorders that are induced by CNS inflammation.