期刊
JOURNAL OF CELL BIOLOGY
卷 169, 期 4, 页码 603-612出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.200502086
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- NIDDK NIH HHS [R01 DK047119, R37 DK047119, DK47119] Funding Source: Medline
- NIEHS NIH HHS [R01 ES008681, ESO8681] Funding Source: Medline
- NINDS NIH HHS [NS34939, R01 NS034939] Funding Source: Medline
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.
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