Abstract
BackgroundMultiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are inflammatory demyelinating and neurodegenerative diseases of the CNS. Although recent studies suggest the neuroprotective effects of oligodendrocytes in neurodegenerative diseases, it remains unknown whether oligodendrocyte death induced by inflammatory attacks contributes to neurodegeneration in MS and EAE. Upon endoplasmic reticulum (ER) stress, activation of pancreatic ER kinase (PERK) promotes cell survival through induction of activating transcription factor 4 (ATF4) by phosphorylating eukaryotic translation initiation factor 2α (eIF2α). We have generated a mouse model that allows for temporally controlled activation of PERK specifically in oligodendrocytes. Our previous study has demonstrated that PERK activation specifically in oligodendrocytes attenuates EAE disease severity and ameliorates EAE-induced oligodendrocyte apoptosis, demyelination, and axon degeneration, without altering inflammation.MethodsWe determined whether oligodendrocyte-specific PERK activation reduced neuron loss in the CNS of EAE mice using the mouse model that allows for temporally controlled activation of PERK specifically in oligodendrocytes. We further generated a mouse model that allows for inactivation of ATF4 specifically in oligodendrocytes, and determined the effects of ATF4 inactivation in oligodendrocytes on mice undergoing EAE.ResultsWe showed that protection of oligodendrocytes resulting from PERK activation led to attenuation of neuron loss in the CNS gray matter of EAE mice. Surprisingly, we found that ATF4 inactivation specifically in oligodendrocytes did not alter EAE disease severity and had no effect on oligodendrocyte loss, demyelination, axon degeneration, neuron loss, and inflammation in EAE mice.ConclusionsThese findings suggest the neuroprotective effects of PERK activation in oligodendrocytes in EAE, and rule out the involvement of ATF4 in oligodendrocytes in the development of EAE. These results imply that the protective effects of PERK activation in oligodendrocytes in MS and EAE are not mediated by ATF4.
Highlights
Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are inflammatory demyelinating and neurodegenerative diseases of the central nervous system (CNS)
pancreatic ER kinase (PERK) activation in oligodendrocytes reduced neuron loss in the CNS of EAE mice Seven-week-old female PLP/Fv2E-PERK mice were immunized with MOG35-55 peptide to induce EAE, and were given i.p. injections of 0.5 mg/kg AP20187 or vehicle daily starting on PID10
Our previous study has demonstrated that AP20187 treatment enhances PERK activation in oligodendrocytes and reduces EAE disease severity and EAE-induced oligodendrocyte apoptosis, demyelination, and axon degeneration, without affecting the inflammatory response [22]
Summary
Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are inflammatory demyelinating and neurodegenerative diseases of the CNS. Our previous study has demonstrated that PERK activation in oligodendrocytes attenuates EAE disease severity and ameliorates EAE-induced oligodendrocyte apoptosis, demyelination, and axon degeneration, without altering inflammation. Our previous study showed that CNS expression of IFN-γ before EAE onset attenuates the disease severity and ameliorates EAE-induced oligodendrocyte loss, demyelination, and axon degeneration in the CNS and that the beneficial effects of IFN-γ in EAE are associated with activation of the PERK pathway in oligodendrocytes and are abrogated in PERK heterozygousdeficient mice [20]. A report showed that oligodendrocytespecific PERK inactivation exacerbates EAE disease severity and aggravates EAE-induced oligodendrocyte loss, demyelination, and axon degeneration in the CNS [21]. Our previous studies showed that activation of PERK in oligodendrocytes protects the cells and myelin against inflammation during EAE [22, 23]. The mechanisms responsible for the cytoprotective effects of the PERK-eIF2α pathway on oligodendrocytes in MS and EAE remain unexplored
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