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

Zhang, Yu; Sheng, Huaxin; Liu, Shuai; Zhao, Shengli; Glembotski, Christopher C.; Warner, David S.; Paschen, Wulf; Yang, Wei

doi:10.1177/0271678x16650218

Cited by 80 publications

(73 citation statements)

References 45 publications

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“…On the other hand, ischemic strokes are the leading cause of death, cognitive and motor dysfunction, and neurodegenerative diseases (Wei et al, 2012). Similarly, ER stress has been found in neurons after ischemic stroke (Yu et al, 2016). …”

Section: Changes Of Er Stress and Autophagy After Traumatic Brain mentioning

confidence: 78%

ER stress and impaired autophagy flux in neuronal degeneration and brain injury

Yin

Sun

et al. 2017

Ageing Research Reviews

176

118

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Autophagy is a highly controlled lysosome-mediated function in eukaryotic cells to eliminate damaged or aged long-lived proteins and organelles. It is required for restoring cellular homeostasis in cell survival under multiple stresses. Autophagy is known to be a double-edged sword because too much activation or inhibition of autophagy can disrupt homeostatic degradation of protein and organelles within the brain and play a role in neuronal cell death. Many factors affect autophagy flux function in the brain, including endoplasmic reticulum (ER) stress, oxidative stress, and aging. Newly emerged research indicates that altered autophagy flux functionality is involved in neurodegeneration of the aged brain, chronic neurological diseases, and after traumatic and ischemic brain injuries. In search to identify neuroprotective agents that may reduce oxidative stress and stimulate autophagy, one particular neuroprotective agent docosahexaenoic acid (DHA) presents unique functions in reducing ER and oxidative stress and modulating autophagy. This review will summarize the recent findings on changes of autophagy in aging, neurodegenerative diseases, and brain injury after trauma or ischemic strokes. Discussion of DHA functions is focused on modulating ER stress and autophagy in regard to its neuroprotection and anti-tumor functions.

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Section: Changes Of Er Stress and Autophagy After Traumatic Brain mentioning

confidence: 78%

ER stress and impaired autophagy flux in neuronal degeneration and brain injury

Yin

Sun

et al. 2017

Ageing Research Reviews

176

118

View full text Add to dashboard Cite

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“…Xbp1 f/f mice (C57BL/6 background) were kindly provided by Dr Laurie Glimcher (Weill Cornell Medical College). 17 To delete Xbp1 in forebrain neurons, we first crossed Xbp1 f/f mice with Emx1 Cre/Cre mice (JAX stock #005628; C57BL/6 background), 8 to generate Xbp1 f/+ ; Emx1-Cre mice. These mice were then mated with homozygous floxed Xbp1 f/f mice to generate experimental animals: Xbp1 f/f ; Emx1-Cre (Xbp1-cKO) and Xbp1 f/f (control).…”

Section: Methodsmentioning

confidence: 99%

“…tMCAO was carried out as described previously. 8 Briefly, anesthesia was induced in mice with 5% isoflurane in 30% O 2 balanced with N 2 O. Mice were then orally intubated and mechanically ventilated with 1.8% isoflurane during surgery.…”

Section: Methodsmentioning

confidence: 99%

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

Jiang

Zhang

et al. 2017

Stroke

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Background and Purpose Impaired protein homeostasis induced by endoplasmic reticulum (ER) dysfunction is a key feature of a variety of age-related brain diseases including stroke. To restore ER function impaired by stress, the unfolded protein response (UPR) is activated. A key UPR pro-survival pathway is controlled by the ER stress sensor inositol-requiring enzyme-1 (IRE1), downstream X-box binding protein-1 (XBP1), and O-linked b-N-acetylglucosamine (O-GlcNAc) modification of proteins (O-GlcNAcylation). Stroke impairs ER function, which activates UPR. 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 (MCAO) in young and aged mice. Thiamet-G was used to increase O-GlcNAcylation. Results Deletion of Xbp1 worsened outcome after transient and permanent MCAO. 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. Pharmacologic 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 UPR branch in stroke outcome. O-GlcNAcylation is a pro-survival pathway that is activated in the stroke penumbra in young mice but impaired in aged mice. Boosting pro-survival 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.

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“…Specifically, expression of target genes of the three UPR branches, including GRP78, GADD153/ CHOP, ER stress protein 72 (ERp72), and PDI, is up-regulated after brain ischemia. [57][58][59][60][61][62][63] Further, splicing of Xbp1 mRNA is activated in post-ischemic brains, 14,64 and eIF2a is phosphorylated in a PERKspecific manner. 65,66 It should be noted that postischemic activation of UPR is unequivocal proof that transient ischemia impairs ER function, and is also an indicator that cells activate adaptive responses to cope with this pathologic state.…”

Section: Brain Ischemiamentioning

confidence: 99%

“…13 Recently, we have reported that a marked increase in expression of GRP78 does not modify the extent of UPR activation triggered by transient cerebral ischemia, which supports a model of UPR activation independent of GRP78 dissociation from ER stress sensor proteins. 14 Under ER stress conditions, the protein folding demand exceeds folding capacity. Activation of UPR triggers a variety of adaptive responses to restore the folding demand/capacity balance, and to clear unfolded/misfolded proteins from the ER, thereby reestablishing cellular homeostasis.…”

Section: Introductionmentioning

confidence: 99%

Unfolded protein response in brain ischemia: A timely update

Yang

Paschen

2016

J Cereb Blood Flow Metab

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Folding and processing newly synthesized proteins are vital functions of the endoplasmic reticulum that are sensitive to a variety of stress conditions. The unfolded protein response is activated to restore endoplasmic reticulum function impaired by stress. While we know that brain ischemia impairs endoplasmic reticulum function, the role of unfolded protein response activation in post-ischemic recovery of neurologic function is only beginning to emerge. Here, we summarize what is known about endoplasmic reticulum stress and unfolded protein response in brain ischemia and discuss recent findings from myocardial ischemia studies that could help to advance research on endoplasmic reticulum stress and unfolded protein response in brain ischemia.

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

Cited by 80 publications

References 45 publications

ER stress and impaired autophagy flux in neuronal degeneration and brain injury

ER stress and impaired autophagy flux in neuronal degeneration and brain injury

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

Unfolded protein response in brain ischemia: A timely update

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