title: PERK activation preserves the viability and function of remyelinating oligodendrocytes in immune-mediated demyelinating diseases.
abstract: Remyelination occurs in multiple sclerosis (MS) lesions but is generally considered to be insufficient. One of the major challenges in MS research is to understand the causes of remyelination failure and to identify therapeutic targets that promote remyelination. Activation of pancreatic endoplasmic reticulum kinase (PERK) signaling in response to endoplasmic reticulum stress modulates cell viability and function under stressful conditions. There is evidence that PERK is activated in remyelinating oligodendrocytes in demyelinated lesions in both MS and its animal model, experimental autoimmune encephalomyelitis (EAE). In this study, we sought to determine the role of PERK signaling in remyelinating oligodendrocytes in MS and EAE using transgenic mice that allow temporally controlled activation of PERK signaling specifically in oligodendrocytes. We demonstrated that persistent PERK activation was not deleterious to myelinating oligodendrocytes in young, developing mice or to remyelinating oligodendrocytes in cuprizone-induced demyelinated lesions. We found that enhancing PERK activation, specifically in (re)myelinating oligodendrocytes, protected the cells and myelin against the detrimental effects of interferon-γ, a key proinflammatory cytokine in MS and EAE. More important, we showed that enhancing PERK activation in remyelinating oligodendrocytes at the recovery stage of EAE promoted cell survival and remyelination in EAE demyelinated lesions. Thus, our data provide direct evidence that PERK activation cell-autonomously enhances the survival and preserves function of remyelinating oligodendrocytes in immune-mediated demyelinating diseases.
authors.affiliation: Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota; Institute for Translational Neuroscience, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Yifeng
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota; Institute for Translational Neuroscience, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Guangcun
authors.initials: G
authors.lastname: Huang
authors.affiliation: Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota; Institute for Translational Neuroscience, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Jamison
authors.affiliation: Department of Ophthalmology, 9th Hospital, Shanghai Jiaotong University School of Medical Science, Shanghai, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Li
authors.affiliation: University of Cambridge Metabolic Research Laboratories, National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, United Kingdom.
authors.forename: Heather P
authors.initials: HP
authors.lastname: Harding
authors.affiliation: University of Cambridge Metabolic Research Laboratories, National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Ron
authors.affiliation: Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota; Institute for Translational Neuroscience, University of Minnesota, Minneapolis, Minnesota. Electronic address: linw@umn.edu.
authors.forename: Wensheng
authors.initials: W
authors.lastname: Lin
mesh_terms: D000818:Animals; D001369:Axons / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003471:Cuprizone; D019610:Cytoprotection / Q000187:drug effects; D003711:Demyelinating Diseases / Q000201:enzymology / Q000276:immunology* / Q000473:pathology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D007249:Inflammation / Q000473:pathology; D007371:Interferon-gamma / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D009186:Myelin Sheath / Q000187:drug effects / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D009836:Oligodendroglia / Q000187:drug effects / Q000201:enzymology / Q000276:immunology / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects; D016559:Tacrolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D014202:Tremor / Q000201:enzymology / Q000473:pathology; D019892:eIF-2 Kinase / Q000378:metabolism*
chemical_list: D003471:Cuprizone; D007371:Interferon-gamma; D016559:Tacrolimus; D019892:eIF-2 Kinase; C463061:AP20187