title: Oligodendrocyte-specific activation of PERK signaling protects mice against experimental autoimmune encephalomyelitis.
abstract: There is compelling evidence that oligodendrocyte apoptosis, in response to CNS inflammation, contributes significantly to the development of the demyelinating disorder multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). Therefore, 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-γ 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 of PERK signaling in oligodendrocytes during EAE. We generated transgenic mice that allow for temporally controlled activation of PERK 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. Importantly, we found that enhanced activation of PERK signaling specifically in oligodendrocytes significantly attenuated EAE disease severity, which was associated with reduced oligodendrocyte apoptosis, demyelination, and axonal degeneration. This effect was not the result of an altered degree of the inflammatory response in EAE mice. Our results provide direct evidence that activation of PERK signaling in oligodendrocytes is cytoprotective, protecting mice against EAE.
authors.affiliation: Department of Cell Biology & Neuroscience, University of South Alabama College of Medicine, Mobile, Alabama 36688, USA. linw@umn.edu
authors.forename: Wensheng
authors.initials: W
authors.lastname: Lin
authors.forename: Yifeng
authors.initials: Y
authors.lastname: Lin
authors.forename: Jin
authors.initials: J
authors.lastname: Li
authors.forename: Ali G
authors.initials: AG
authors.lastname: Fenstermaker
authors.forename: Sharon W
authors.initials: SW
authors.lastname: Way
authors.forename: Benjamin
authors.initials: B
authors.lastname: Clayton
authors.forename: Stephanie
authors.initials: S
authors.lastname: Jamison
authors.forename: Heather P
authors.initials: HP
authors.lastname: Harding
authors.forename: David
authors.initials: D
authors.lastname: Ron
authors.forename: Brian
authors.initials: B
authors.lastname: Popko
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000473:pathology; D001973:Bromodeoxyuridine / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism* / Q000628:therapy*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology; D020287:In Situ Nick-End Labeling; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D004676:Myelin Basic Protein / Q000378:metabolism; D018991:Myelin Proteolipid Protein / Q000235:genetics; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000235:genetics; D009836:Oligodendroglia / Q000187:drug effects / Q000378:metabolism / Q000502:physiology* / Q000648:ultrastructure; D054645:Protein Phosphatase 1 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013234:Stem Cells / Q000187:drug effects / Q000502:physiology; D013601:T-Lymphocytes / Q000187:drug effects / Q000502:physiology; D016559:Tacrolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D013997:Time Factors; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism*
chemical_list: D001973:Bromodeoxyuridine; D016207:Cytokines; D007166:Immunosuppressive Agents; D004676:Myelin Basic Protein; D018991:Myelin Proteolipid Protein; D054645:Protein Phosphatase 1; D012333:RNA, Messenger; D020794:Receptor Protein-Tyrosine Kinases; D016559:Tacrolimus; D051742:Transcription Factor CHOP; D019892:eIF-2 Kinase; C463061:AP20187; C497250:Ddit3 protein, mouse; C499047:Mbp protein, mouse; C047516:Plp1 protein, mouse; C080835:RON protein; C513256:Ppp1r15a protein, mouse
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