Oligodendrocyte-Specific Activation of PERK Signaling Protects Mice Against Experimental Autoimmune Encephalomyelitis
5980 • The Journal of Neuroscience, April 3, 2013 • 33(14):5980–5991 Neurobiology of Disease Oligodendrocyte-Specific Activation of PERK Signaling Protects Mice against Experimental Autoimmune Encephalomyelitis Wensheng Lin,1,2 Yifeng Lin,1 Jin Li,1 Ali G. Fenstermaker,3 Sharon W. Way,3 Benjamin Clayton,3 Stephanie Jamison,1 Heather P. Harding,4 David Ron,4 and Brian Popko3 1Department of Cell Biology & Neuroscience, University of South Alabama College of Medicine, Mobile, Alabama 36688, 2Department of Comparative Medicine, University of South Alabama College of Medicine, Mobile, Alabama 36688, 3Department of Neurology, University of Chicago, Chicago, Illinois 60637, and 4University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Cambridge CB20QQ, United Kingdom There is compelling evidence that oligodendrocyte apoptosis, in response to CNS inflammation, contributes significantly to the develop- ment of the demyelinating disorder multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). There- fore, approaches designed to protect oligodendrocytes would likely have therapeutic value. Activation of pancreatic endoplasmic reticulum kinase (PERK) signaling in response to endoplasmic reticulum (ER) stress increases cell survival under various cytotoxic conditions. Moreover, there is evidence that PERK signaling is activated in oligodendrocytes within demyelinating lesions in multiple sclerosis and EAE. Our previous study demonstrated that CNS delivery of the inflammatory cytokine interferon-␥ before EAE onset protected mice against EAE, and this protection was dependent on PERK signaling. In our current study, we sought to elucidate the role ofPERKsignalinginoligodendrocytesduringEAE.WegeneratedtransgenicmicethatallowfortemporallycontrolledactivationofPERK signaling, in the absence of ER stress, specifically in oligodendrocytes. We demonstrated that persistent activation of PERK signaling was not deleterious to oligodendrocyte viability or the myelin of adult animals.
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