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Activation of the ATF6 branch of the unfolded protein response in neurons improves stroke outcome.

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Date
2017-03
Authors
Yu, Zhui
Sheng, Huaxin
Liu, Shuai
Zhao, Shengli
Glembotski, Christopher C
Warner, David S
Paschen, Wulf
Yang, Wei
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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.
Type
Journal article
Subject
Neurons
Animals
Mice
Brain Infarction
Infarction, Middle Cerebral Artery
Recovery of Function
Autophagy
Activating Transcription Factor 6
Stroke
Gene Knock-In Techniques
Unfolded Protein Response
Neuroprotection
Permalink
https://hdl.handle.net/10161/23259
Published Version (Please cite this version)
10.1177/0271678x16650218
Publication Info
Yu, Zhui; Sheng, Huaxin; Liu, Shuai; Zhao, Shengli; Glembotski, Christopher C; Warner, David S; ... Yang, Wei (2017). Activation of the ATF6 branch of the unfolded protein response in neurons improves stroke outcome. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism, 37(3). pp. 1069-1079. 10.1177/0271678x16650218. Retrieved from https://hdl.handle.net/10161/23259.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
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Scholars@Duke

Wulf Paschen

Professor in Anesthesiology
My research interests are understanding the mechanisms underlying induction of cell death induced by a severe form of cellular stress. I am particularly interested in the role of the endoplasmic reticulum in the pathological process induced by transient cerebral ischemia and culminating in neuronal cell death. This pathological process is associated with an irreversible suppression of protein synthese that limits the ability of cells to withstand ischemia-induced impairment of endoplasmic r
Sheng

Huaxin Sheng

Associate Professor in Anesthesiology
We have successfully developed various rodent models of brain and spinal cord injuries in our lab, such as focal cerebral ischemia, global cerebral ischemia, head trauma, subarachnoid hemorrhage, intracerebral hemorrhage, spinal cord ischemia and compression injury. We also established cardiac arrest and hemorrhagic shock models for studying multiple organ dysfunction.  Our current studies focus on two projects. One is to examine the efficacy of catalytic antioxidant in treating cerebral is
Warner

David Samuel Warner

Distinguished Distinguished Professor of Anesthesiology, in the School of Medicine
Humans may sustain a variety of forms of acute central nervous system injury including ischemia, trauma, vasospasm, and perinatal hypoxemia. The Multidisciplinary Neuroprotection Laboratories is dedicated to examining the pathophysiology of acute brain and spinal cord injury with particular reference to disease states managed in the perioperative or neurointensive care environments. Rodent recovery models of cerebral ischemia, traumatic brain injury, cardiopulmonary bypass, subarachnoid he
This author no longer has a Scholars@Duke profile, so the information shown here reflects their Duke status at the time this item was deposited.
Yang

Wei Yang

Associate Professor in Anesthesiology
Alphabetical list of authors with Scholars@Duke profiles.
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