期刊
JOURNAL OF NEUROCHEMISTRY
卷 132, 期 3, 页码 342-353出版社
WILEY-BLACKWELL
DOI: 10.1111/jnc.12981
关键词
astrogliosis; brain ischemia; ER stress; neuronal death
资金
- Ministry of Education, Science, Technology, Sports and Culture of Japan [24500419]
- Grants-in-Aid for Scientific Research [24500419, 26430069] Funding Source: KAKEN
To dissect the role of endoplasmic reticulum (ER) stress and unfolded protein response in brain ischemia, we investigated the relevance of activating transcription factor 6 (ATF6), a master transcriptional factor in the unfolded protein response, after permanent middle cerebral artery occlusion (MCAO) in mice. Enhanced expression of glucose-regulated protein78, a downstream molecular chaperone of ATF6, was observed in both neurons and glia in the peri-infarct region of wild-type mice after MCAO. Analysis using wild-type and Atf6(-/-) mice revealed a larger infarct volume and increased cell death in the peri-ischemic region of Atf6(-/-) mice 5days after MCAO. These phenotypes in Atf6(-/-) mice were associated with reduced levels of astroglial activation/glial scar formation, and a spread of tissue damage into the non-infarct area. Further analysis in mice and cultured astrocytes revealed that signal transducer and activator of transcription 3 (STAT3)-glial fibrillary acidic protein signaling were diminished in Atf6(-/-) astrocytes. A chemical chaperone, 4-phenylbutyrate, restored STAT3-glial fibrillary acidic protein signaling, while ER stressors, such as tunicamycin and thapsigargin, almost completely abolished signaling in cultured astrocytes. Furthermore, ER stress-induced deactivation of STAT3 was mediated, at least in part, by the ER stress-responsive tyrosine phosphatase, TC-PTP/PTPN2. These results suggest that ER stress plays critical roles in determining the level of astroglial activation and neuronal survival after brain ischemia
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