Endoplasmic reticulum stress modulates the response of myelinating oligodendrocytes to the immune cytokine interferon-gamma.
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.
Lin
Wensheng
W
Jack Miller Center for Peripheral Neuropathy, Department of Neurology, University of Chicago, Chicago, IL 60637, USA.
Harding
Heather P
HP
Ron
David
D
Popko
Brian
B
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D003711:Demyelinating Diseases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D004660:Encephalitis / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000276:immunology / Q000378:metabolism*; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005260:Female; D006706:Homeostasis; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D009154:Mutation / Q000235:genetics; D009186:Myelin Sheath / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D009836:Oligodendroglia / Q000276:immunology / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D013312:Stress, Physiological / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism
D015852:Eukaryotic Initiation Factor-2; D007371:Interferon-gamma; D019892:eIF-2 Kinase