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.
Type
Journal articleSubject
NeuronsAnimals
Mice
Brain Infarction
Infarction, Middle Cerebral Artery
Recovery of Function
Autophagy
Activating Transcription Factor 6
Stroke
Gene Knock-In Techniques
Unfolded Protein Response
Neuroprotection
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https://hdl.handle.net/10161/23259Published Version (Please cite this version)
10.1177/0271678x16650218Publication 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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Show full item recordScholars@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
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
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.
Wei Yang
Associate Professor in Anesthesiology
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