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

Wensheng Lin¹, Heather P. Harding², David Ron², , and Brian Popko¹

¹ Jack Miller Center for Peripheral Neuropathy, Department of Neurology, University of Chicago, Chicago, IL 60637
² The Skirball Institute, New York University School of Medicine, New York, NY 10016

Correspondence to Brian Popko: bpopko{at}neurology.bsd.uchicago.edu

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

Abbreviations used in this paper: ATF, activating transcription factor; BIP, binding immunoglobulin protein; CGT, ceramide galactosyltransferase; CHOP, CAATT enhancer–binding protein homologous protein; CNP, 2'3'-cyclic nucleotide 3'-phosphodiesterase; CNS, central nervous system; GFAP, glial fibrillary acidic protein; E 14, embryonic day 14; eIF, eukaryotic translation initiation factor; IFN-, interferon-; iNOS, inducible NO synthase; IRE, inositol requiring; MBP, myelin basic protein; MHC, major histocompatibility complex; MS, multiple sclerosis; NO, nitric oxide; PERK, pancreatic ER kinase; PLP, proteolipid protein; PMD, Pelizaeus-Merzbacher disease; tTA, tetracycline-controlled transactivator; VWM, leukoencephalopathy with vanishing white matter.

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