title: Deletion of Atf6α impairs astroglial activation and enhances neuronal death following brain ischemia in mice.
abstract: To dissect the role of endoplasmic reticulum (ER) stress and unfolded protein response in brain ischemia, we investigated the relevance of activating transcription factor 6α (ATF6α), 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 ATF6α, was observed in both neurons and glia in the peri-infarct region of wild-type mice after MCAO. Analysis using wild-type and Atf6α(-/-) mice revealed a larger infarct volume and increased cell death in the peri-ischemic region of Atf6α(-/-) mice 5 days after MCAO. These phenotypes in Atf6α(-/-) 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 Atf6α(-/-) 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.
authors.affiliation: Department of Neurosurgery, Graduate School of Medical Sciences, Kanazawa University, Kanazawa City, Ishikawa, Japan.
authors.forename: Akifumi
authors.initials: A
authors.lastname: Yoshikawa
authors.forename: Tomoya
authors.initials: T
authors.lastname: Kamide
authors.forename: Koji
authors.initials: K
authors.lastname: Hashida
authors.forename: Hieu Minh
authors.initials: HM
authors.lastname: Ta
authors.forename: Yuki
authors.initials: Y
authors.lastname: Inahata
authors.forename: Mika
authors.initials: M
authors.lastname: Takarada-Iemata
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Hattori
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Mori
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Takahashi
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Matsuyama
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Kitao
authors.forename: Osamu
authors.initials: O
authors.lastname: Hori
mesh_terms: D051702:Activating Transcription Factor 6 / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001253:Astrocytes / Q000473:pathology*; D002545:Brain Ischemia / Q000473:pathology*; D016923:Cell Death / Q000235:genetics; D002478:Cells, Cultured; D017353:Gene Deletion; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D008262:Macrophage Activation / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000473:pathology*; D058767:Protein Unfolding; D050796:STAT3 Transcription Factor / Q000378:metabolism
chemical_list: D051702:Activating Transcription Factor 6; C497112:Atf6 protein, mouse; D005904:Glial Fibrillary Acidic Protein; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse
keywords: ER stress; astrogliosis; brain ischemia; neuronal death