Published online before print September 25, 2008

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(American Journal of Pathology. 2008;173:1508-1517.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.080449

Enhanced Integrated Stress Response Promotes Myelinating Oligodendrocyte Survival in Response to Interferon-

Wensheng Lin^*, Phillip E. Kunkler^*, Heather P. Harding, David Ron, Richard P. Kraig^* and Brian Popko^*

From the Department of Neurology,^* The University of Chicago, Chicago, Illinois; and The Skirball Institute, New York University School of Medicine, New York, New York

The T-cell-derived, pleiotropic cytokine interferon (IFN)- is believed to play a key regulatory role in immune-mediated demyelinating disorders of the central nervous system, including multiple sclerosis and experimental autoimmune encephalomyelitis. Our previous work has demonstrated that the endoplasmic reticulum (ER) stress response modulates the response of oligodendrocytes to this cytokine. The ER stress response activates the pancreatic ER kinase, which coordinates an adaptive program known as the integrated stress response by phosphorylating translation initiation factor 2 (eIF2). In this study, we found that growth arrest and DNA damage 34 (GADD34), a stress-inducible regulatory subunit of a phosphatase complex that dephosphorylates eIF2, was selectively up-regulated in myelinating oligodendrocytes in mice that ectopically expressed IFN- in the central nervous system. We also found that a GADD34 mutant strain of mice displayed increased levels of phosphorylated eIF2 (p-eIF2) in myelinating oligodendrocytes when exposure to IFN-, as well as diminished oligodendrocyte loss and hypomyelination. Furthermore, treatment with salubrinal, a small chemical compound that specifically inhibits protein phosphatase 1(PP1)-GADD34 phosphatase activity, increased the levels of p-eIF2 and ameliorated hypomyelination and oligodendrocyte loss in cultured hippocampal slices exposed to IFN-. Thus, our data provide evidence that an enhanced integrated stress response could promote oligodendrocyte survival in immune-mediated demyelination diseases.