Deletion of Atf6[alpha] impairs astroglial activation and enhances neuronal death following brain ischemia in mice

• Published in: Journal of neurochemistry 2015-02, Vol.132 (3), p.342
• Main Authors: Yoshikawa, Akifumi, Kamide, Tomoya, Hashida, Koji, Ta, Hieu Minh, Inahata, Yuki, Takarada-Iemata, Mika, Hattori, Tsuyoshi, Mori, Kazutoshi, Takahashi, Ryosuke, Matsuyama, Tomohiro, Hayashi, Yutaka, Kitao, Yasuko, Hori, Osamu
• Format: Article
• Language: English
• Subjects: Endoplasmic reticulum; Ischemia; Neurochemistry; Rodents; Signal transduction; Transcription factors
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.12981

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[alpha] (ATF6[alpha]), 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[alpha], was observed in both neurons and glia in the peri-infarct region of wild-type mice after MCAO. Analysis using wild-type and Atf6[alpha]-/- mice revealed a larger infarct volume and increased cell death in the peri-ischemic region of Atf6[alpha]-/- mice 5 days after MCAO. These phenotypes in Atf6[alpha]-/- 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[alpha]-/- 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 ATF6[alpha]--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.