title: Activation of the ATF6 branch of the unfolded protein response in neurons improves stroke outcome.
abstract: Impaired function of the endoplasmic reticulum (ER stress) is a hallmark of many human diseases including stroke. To restore ER function in stressed cells, the unfolded protein response (UPR) is induced, which activates 3 ER stress sensor proteins including activating transcription factor 6 (ATF6). ATF6 is then cleaved by proteases to form the short-form ATF6 (sATF6), a transcription factor. To determine the extent to which activation of the ATF6 UPR branch defines the fate and function of neurons after stroke, we generated a conditional and tamoxifen-inducible sATF6 knock-in mouse. To express sATF6 in forebrain neurons, we crossed our sATF6 knock-in mouse line with Emx1-Cre mice to generate ATF6-KI mice. After the ATF6 branch was activated in ATF6-KI mice with tamoxifen, mice were subjected to transient middle cerebral artery occlusion. Forced activation of the ATF6 UPR branch reduced infarct volume and improved functional outcome at 24 h after stroke. Increased autophagic activity at early reperfusion time after stroke may contribute to the ATF6-mediated neuroprotection. We concluded that the ATF6 UPR branch is crucial to ischemic stroke outcome. Therefore, boosting UPR pro-survival pathways may be a promising therapeutic strategy for stroke.
authors.affiliation: 1 Multidisciplinary Neuroprotection Laboratories, Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA.|2 Department of Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.
authors.forename: Zhui
authors.initials: Z
authors.lastname: Yu
authors.affiliation: 1 Multidisciplinary Neuroprotection Laboratories, Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA.
authors.forename: Huaxin
authors.initials: H
authors.lastname: Sheng
authors.affiliation: 1 Multidisciplinary Neuroprotection Laboratories, Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA.
authors.forename: Shuai
authors.initials: S
authors.lastname: Liu
authors.affiliation: 3 Department of Neurobiology, Duke University Medical Center, Durham, NC, USA.
authors.forename: Shengli
authors.initials: S
authors.lastname: Zhao
authors.affiliation: 4 San Diego State University Heart Institute and the Department of Biology, San Diego, CA, USA.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Glembotski
authors.affiliation: 1 Multidisciplinary Neuroprotection Laboratories, Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Warner
authors.affiliation: 1 Multidisciplinary Neuroprotection Laboratories, Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA.
authors.forename: Wulf
authors.initials: W
authors.lastname: Paschen
authors.affiliation: 1 Multidisciplinary Neuroprotection Laboratories, Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Yang
mesh_terms: D051702:Activating Transcription Factor 6 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001343:Autophagy; D020520:Brain Infarction; D055879:Gene Knock-In Techniques; D020244:Infarction, Middle Cerebral Artery; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D000066829:Neuroprotection / Q000187:drug effects*; D020127:Recovery of Function; D020521:Stroke / Q000188:drug therapy*; D056811:Unfolded Protein Response
chemical_list: D051702:Activating Transcription Factor 6; C497112:Atf6 protein, mouse
keywords: Brain ischemia; endoplasmic reticulum stress; neuroprotection; transgenic mice; unfolded protein response