Enhanced integrated stress response promotes myelinating oligodendrocyte survival in response to interferon-γ

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

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76 Scopus citations


The T-cell-derived, pleiotropic cytokine interferon (IFN)-γ 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 2α (eIF2α). In this study, we found that growth arrest and DNA damage 34 (GADD34), a stress-inducible regulatory subunit of a phosphatase complex that dephosphorylates eIF2α, was selectively up-regulated in myelinating oligodendrocytes in mice that ectopically expressed IFN-γ in the central nervous system. We also found that a GADD34 mutant strain of mice displayed increased levels of phosphorylated eIF2α (p-eIF2α) in myelinating oligodendrocytes when exposure to IFN-γ, 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-eIF2α and ameliorated hypomyelination and oligodendrocyte loss in cultured hippocampal slices exposed to IFN-γ. Thus, our data provide evidence that an enhanced integrated stress response could promote oligodendrocyte survival in immune-mediated demyelination diseases.

Original languageEnglish (US)
Pages (from-to)1508-1517
Number of pages10
JournalAmerican Journal of Pathology
Issue number5
StatePublished - Nov 2008
Externally publishedYes

Bibliographical note

Funding Information:
Supported by the National Institutes of Health (grants NS34939 to B.P., NS19108 to R.P.K., and DK47119 and ES08681 to D.R. ), the American Heart Association (to R.P.K.), the White Foundation (to R.P.K.), the Myelin Repair Foundation (to B.P.), and the National Multiple Sclerosis Society (career transition fellowship Grant TA 3026-A-1 to W.L. ).


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