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XBP1 (X-Box-Binding Protein-1)-Dependent O-GlcNAcylation Is Neuroprotective in Ischemic Stroke in Young Mice and Its Impairment in Aged Mice Is Rescued by Thiamet-G.
Abstract
<h4>Background and purpose</h4>Impaired protein homeostasis induced by endoplasmic
reticulum dysfunction is a key feature of a variety of age-related brain diseases
including stroke. To restore endoplasmic reticulum function impaired by stress, the
unfolded protein response is activated. A key unfolded protein response prosurvival
pathway is controlled by the endoplasmic reticulum stress sensor (inositol-requiring
enzyme-1), XBP1 (downstream X-box-binding protein-1), and O-GlcNAc (O-linked β-N-acetylglucosamine)
modification of proteins (O-GlcNAcylation). Stroke impairs endoplasmic reticulum function,
which activates unfolded protein response. The rationale of this study was to explore
the potentials of the IRE1/XBP1/O-GlcNAc axis as a target for neuroprotection in ischemic
stroke.<h4>Methods</h4>Mice with Xbp1 loss and gain of function in neurons were generated. Stroke was induced by transient
or permanent occlusion of the middle cerebral artery in young and aged mice. Thiamet-G
was used to increase O-GlcNAcylation.<h4>Results</h4>Deletion of Xbp1 worsened outcome after transient and permanent middle cerebral artery occlusion.
After stroke, O-GlcNAcylation was activated in neurons of the stroke penumbra in young
mice, which was largely Xbp1 dependent. This activation of O-GlcNAcylation was impaired
in aged mice. Pharmacological increase of O-GlcNAcylation before or after stroke improved
outcome in both young and aged mice.<h4>Conclusions</h4>Our study indicates a critical
role for the IRE1/XBP1 unfolded protein response branch in stroke outcome. O-GlcNAcylation
is a prosurvival pathway that is activated in the stroke penumbra in young mice but
impaired in aged mice. Boosting prosurvival pathways to counterbalance the age-related
decline in the brain's self-healing capacity could be a promising strategy to improve
ischemic stroke outcome in aged brains.
Type
Journal articleSubject
AnimalsMice, Inbred C57BL
Mice, Transgenic
Mice
Brain Ischemia
Infarction, Middle Cerebral Artery
Disease Models, Animal
Pyrans
Thiazoles
Protein-Serine-Threonine Kinases
Acetylglucosamine
Membrane Proteins
Age Factors
Protein Folding
Male
Stroke
Unfolded Protein Response
Neuroprotection
X-Box Binding Protein 1
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https://hdl.handle.net/10161/23255Published Version (Please cite this version)
10.1161/strokeaha.117.016579Publication Info
Jiang, Meng; Yu, Shu; Yu, Zhui; Sheng, Huaxin; Li, Ying; Liu, Shuai; ... Yang, Wei (2017). XBP1 (X-Box-Binding Protein-1)-Dependent O-GlcNAcylation Is Neuroprotective in Ischemic
Stroke in Young Mice and Its Impairment in Aged Mice Is Rescued by Thiamet-G. Stroke, 48(6). pp. 1646-1654. 10.1161/strokeaha.117.016579. Retrieved from https://hdl.handle.net/10161/23255.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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