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

Wensheng Lin, Heather P. Harding, David Ron, Brian Popko*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

147 Scopus citations

Abstract

Interferon-γ (IFN-γ) 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-γ 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-γ in the central nervous system (CNS). Compared with a wild-type genetic background, the enforced expression of IFN-γ 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 2α and specifically maintains client protein homeostasis in the stressed ER. Therefore, the hypersensitivity of PERK+/- mice to IFN-γ implicates ER stress in demyelinating disorders that are induced by CNS inflammation.

Original languageEnglish (US)
Pages (from-to)603-612
Number of pages10
JournalJournal of Cell Biology
Volume169
Issue number4
DOIs
StatePublished - May 2005

ASJC Scopus subject areas

  • Cell Biology

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