Oligodendrocytes, which produce the myelin that insulates axons in the central nervous system (CNS), are highly sensitive to conditions that disrupt protein synthesis, and some human demyelinating diseases are associated with mutations in genes encoding components responsible for protein synthesis. Lin et al. provide evidence that exposure of oligodendrocytes to interferon-γ (IFN-γ)--produced by T cells and natural killer cells and implicated in immune-mediated demyelinating diseases such as multiple sclerosis--activates the endoplasmic reticulum (ER) stress response and that this may contribute to cell death. Cultured oligodendrocytes underwent apoptosis upon exposure to IFN-γ. The ER stress response was detected as an increase in the abundance of CHOP (a transcription factor) and BiP (an ER chaperone), increased phosphorylation of eukaryotic initiation factor 2α (eIF-2α), and activation of caspase-12. The authors used a transgenic mouse designed for inducible expression of IFN-γ in astrocytes of the CNS and showed that when expression of INF-γ was induced during embryogenesis, 14-day-old mice contained axons that were hypomyelinated and oligodendrocytes that exhibited characteristics of activation of the ER stress response. These IFN-γ-engineered mice were crossed with mice deficient for pancreatic ER kinase (PERK), which is activated in response to ER stress and phosphorylates eIF-2α, thus attenuating protein synthesis. PERK+/– mice expressing CNS IFN-γ exhibited tremor, ataxia, and seizures and had axons that were more severely hypomyelinated than those of wild-type mice expressing IFN-γ in the CNS. In addition, the abundance of apoptotic oligodendrocytes was higher in the PERK+/– mice expressing CNS IFN-γ, and the overall number of oligodendrocytes was fewer. Oligodendrocytes of adult mice in which expression of IFN-γ was induced did not show any decrease in myelination and only had evidence of a modest activation of the ER stress response. This is likely due to the decreased protein and lipid synthesis required to maintain myelin in the adult compared with the more demanding requirements for synthesis of myelin during development.
W. Lin, H. P. Harding, D. Ron, B. Popko, Endoplasmic reticulum stress modulates the response of myelinating oligodendrocytes to the immune cytokine interferon-γ. J. Cell Biol. 169, 603-612 (2005). [Abstract] [Full Text]