Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 117, Issue 2, Pages 448-456Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI29571
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Funding
- NIDDK NIH HHS [DK47119, R37 DK047119, R01 DK047119] Funding Source: Medline
- NIEHS NIH HHS [ES08681, R01 ES008681] Funding Source: Medline
- NINDS NIH HHS [NS34939, R01 NS034939] Funding Source: Medline
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In response to ER stress, the pancreatic endoplasmic reticulum kinase (PERK) coordinates an adaptive program known as the integrated stress response (ISR) by phosphorylating the a subunit of eukaryotic translation initiation factor 2 (eIF2 alpha). IFN-gamma, which activates the ER stress response in oligodendrocytes, is believed to play a critical role in the immune-mediated CNS disorder multiple sclerosis (MS) and its mouse model, experimental autoimmune encephalomyelitis (EAE). Here we report that CNS delivery of IFN-gamma before EAE onset ameliorated the disease course and prevented demyelination, axonal damage, and oligodendrocyte loss. The beneficial effects of IFN-gamma were accompanied by PERK activation in oligodendrocytes and were abrogated in PERK-deficient animals. Our results indicate that IFN-gamma activation of PERK in mature oligodendrocytes attenuates EAE severity and suggest that therapeutic approaches to activate the ISR could prove beneficial
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