Oligodendrocyte-specific ATF4 inactivation does not influence the development of EAE
Abstract Background Multiple 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,...
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| Format: | Article |
| Language: | English |
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BMC
2019-02-01
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| Series: | Journal of Neuroinflammation |
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| Online Access: | http://link.springer.com/article/10.1186/s12974-019-1415-6 |
| _version_ | 1818064556331630592 |
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| author | Yuan Yue Milos Stanojlovic Yifeng Lin Gerard Karsenty Wensheng Lin |
| author_facet | Yuan Yue Milos Stanojlovic Yifeng Lin Gerard Karsenty Wensheng Lin |
| author_sort | Yuan Yue |
| collection | DOAJ |
| description | Abstract Background Multiple 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. Methods We 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. Results We 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. Conclusions These 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. |
| first_indexed | 2024-12-10T14:37:52Z |
| format | Article |
| id | doaj.art-338427acb0bd4671b31d8458d7b203f4 |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-12-10T14:37:52Z |
| publishDate | 2019-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-338427acb0bd4671b31d8458d7b203f42022-12-22T01:44:47ZengBMCJournal of Neuroinflammation1742-20942019-02-0116111510.1186/s12974-019-1415-6Oligodendrocyte-specific ATF4 inactivation does not influence the development of EAEYuan Yue0Milos Stanojlovic1Yifeng Lin2Gerard Karsenty3Wensheng Lin4Department of Neuroscience, University of MinnesotaDepartment of Neuroscience, University of MinnesotaDepartment of Neuroscience, University of MinnesotaDepartment of Genetics and Development, Columbia University Medical CenterDepartment of Neuroscience, University of MinnesotaAbstract Background Multiple 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. Methods We 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. Results We 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. Conclusions These 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.http://link.springer.com/article/10.1186/s12974-019-1415-6Multiple sclerosisEAEPERKATF4NeurodegenerationOligodendrocyte |
| spellingShingle | Yuan Yue Milos Stanojlovic Yifeng Lin Gerard Karsenty Wensheng Lin Oligodendrocyte-specific ATF4 inactivation does not influence the development of EAE Journal of Neuroinflammation Multiple sclerosis EAE PERK ATF4 Neurodegeneration Oligodendrocyte |
| title | Oligodendrocyte-specific ATF4 inactivation does not influence the development of EAE |
| title_full | Oligodendrocyte-specific ATF4 inactivation does not influence the development of EAE |
| title_fullStr | Oligodendrocyte-specific ATF4 inactivation does not influence the development of EAE |
| title_full_unstemmed | Oligodendrocyte-specific ATF4 inactivation does not influence the development of EAE |
| title_short | Oligodendrocyte-specific ATF4 inactivation does not influence the development of EAE |
| title_sort | oligodendrocyte specific atf4 inactivation does not influence the development of eae |
| topic | Multiple sclerosis EAE PERK ATF4 Neurodegeneration Oligodendrocyte |
| url | http://link.springer.com/article/10.1186/s12974-019-1415-6 |
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