Abstract
Interferon-gamma (IFN-gamma) is believed to contribute to immune-mediated demyelinating disorders by targeting the myelin-producing 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 oligodendrocytes 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 2alpha 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.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Animals
-
Animals, Newborn
-
Apoptosis / genetics
-
Apoptosis / immunology
-
Demyelinating Diseases / genetics
-
Demyelinating Diseases / immunology
-
Demyelinating Diseases / metabolism*
-
Encephalitis / genetics
-
Encephalitis / immunology
-
Encephalitis / metabolism*
-
Endoplasmic Reticulum / immunology
-
Endoplasmic Reticulum / metabolism*
-
Eukaryotic Initiation Factor-2 / genetics
-
Eukaryotic Initiation Factor-2 / immunology
-
Eukaryotic Initiation Factor-2 / metabolism
-
Female
-
Homeostasis
-
Interferon-gamma / genetics
-
Interferon-gamma / immunology
-
Interferon-gamma / metabolism*
-
Male
-
Mice
-
Mice, Knockout
-
Mice, Transgenic
-
Microscopy, Electron, Transmission
-
Mutation / genetics
-
Myelin Sheath / metabolism
-
Myelin Sheath / pathology
-
Myelin Sheath / ultrastructure
-
Oligodendroglia / immunology
-
Oligodendroglia / metabolism*
-
Phosphorylation
-
Rats
-
Stress, Physiological / genetics
-
Stress, Physiological / immunology
-
Stress, Physiological / metabolism*
-
eIF-2 Kinase / genetics
-
eIF-2 Kinase / metabolism
Substances
-
Eukaryotic Initiation Factor-2
-
Interferon-gamma
-
PERK kinase
-
eIF-2 Kinase