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

dc.contributor.author

Yu, Zhui

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Sheng, Huaxin

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Liu, Shuai

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Zhao, Shengli

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Glembotski, Christopher C

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Warner, David S

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Paschen, Wulf

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Yang, Wei

dc.date.accessioned

2021-06-01T13:56:15Z

dc.date.available

2021-06-01T13:56:15Z

dc.date.issued

2017-03

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2021-06-01T13:56:15Z

dc.description.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.

dc.identifier

0271678X16650218

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0271-678X

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1559-7016

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https://hdl.handle.net/10161/23259

dc.language

eng

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SAGE Publications

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Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism

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10.1177/0271678x16650218

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Neurons

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Animals

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Mice

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Brain Infarction

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Infarction, Middle Cerebral Artery

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Recovery of Function

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Autophagy

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Activating Transcription Factor 6

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Stroke

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Gene Knock-In Techniques

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Unfolded Protein Response

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Neuroprotection

dc.title

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

dc.type

Journal article

duke.contributor.orcid

Sheng, Huaxin|0000-0002-4325-2940

duke.contributor.orcid

Yang, Wei|0000-0001-5719-4393

pubs.begin-page

1069

pubs.end-page

1079

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3

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Faculty

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Duke

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School of Medicine

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Anesthesiology

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Clinical Science Departments

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Neurobiology

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Duke Institute for Brain Sciences

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Surgery

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Anesthesiology, Neuroanesthesia

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Basic Science Departments

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University Institutes and Centers

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Institutes and Provost's Academic Units

pubs.publication-status

Published

pubs.volume

37

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