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
Autor: | Huaxin Sheng, Ying Li, Zhui Yu, Wei Yang, Meng Jiang, Shuai Liu, David S. Warner, Shu Yu, Wulf Paschen |
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Rok vydání: | 2017 |
Předmět: |
Male
X-Box Binding Protein 1 0301 basic medicine Protein Folding medicine.medical_specialty XBP1 Mice Transgenic Protein Serine-Threonine Kinases Neuroprotection Article Acetylglucosamine Brain Ischemia Brain ischemia Mice 03 medical and health sciences 0302 clinical medicine Internal medicine medicine.artery Animals Medicine Stroke Pyrans Advanced and Specialized Nursing business.industry Endoplasmic reticulum Penumbra Age Factors Membrane Proteins Infarction Middle Cerebral Artery medicine.disease Surgery Mice Inbred C57BL Disease Models Animal Thiazoles 030104 developmental biology Endocrinology Middle cerebral artery Unfolded Protein Response Unfolded protein response Neurology (clinical) Cardiology and Cardiovascular Medicine business 030217 neurology & neurosurgery |
Zdroj: | Stroke. 48:1646-1654 |
ISSN: | 1524-4628 0039-2499 |
Popis: | Background and Purpose— 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. Methods— 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. Results— 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. Conclusions— 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. |
Databáze: | OpenAIRE |
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