| First Author | Yoshikawa A | Year | 2015 |
| Journal | J Neurochem | Volume | 132 |
| Issue | 3 | Pages | 342-53 |
| PubMed ID | 25351847 | Mgi Jnum | J:218276 |
| Mgi Id | MGI:5617106 | Doi | 10.1111/jnc.12981 |
| Citation | Yoshikawa A, et al. (2015) Deletion of Atf6alpha impairs astroglial activation and enhances neuronal death following brain ischemia in mice. J Neurochem 132(3):342-53 |
| abstractText | To dissect the role of endoplasmic reticulum (ER) stress and unfolded protein response in brain ischemia, we investigated the relevance of activating transcription factor 6alpha (ATF6alpha), 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 ATF6alpha, was observed in both neurons and glia in the peri-infarct region of wild-type mice after MCAO. Analysis using wild-type and Atf6alpha(-/-) mice revealed a larger infarct volume and increased cell death in the peri-ischemic region of Atf6alpha(-/-) mice 5 days after MCAO. These phenotypes in Atf6alpha(-/-) 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 Atf6alpha(-/-) 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. We here suggest a mechanism triggered after brain ischemia in which the enhanced level of endoplasmic reticulum (ER) stress-caused by deletion of the activating transcription factor ATF6alpha-leads to suppression of the STAT3-GFAP signaling, inhibition of astroglial activation/glial scar formation, and enhanced level of neuronal death in the peri-ischemic area. This is mediated, at least in part, through the ER stress-responsive tyrosine phosphatase, TC-PTP. CNTF, ciliary neurotrophic factor; GFAP, Glial fibrillary acidic protein; IL-6, interleukin 6; LIF, leukemia inhibitory factor; STAT3, signal transducer, and activator of transcription 3. |
