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

Publication ,  Journal Article
Yu, Z; Sheng, H; Liu, S; Zhao, S; Glembotski, CC; Warner, DS; Paschen, W; Yang, W
Published in: J Cereb Blood Flow Metab
March 2017

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.

Duke Scholars

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Published In

J Cereb Blood Flow Metab

DOI

EISSN

1559-7016

Publication Date

March 2017

Volume

37

Issue

3

Start / End Page

1069 / 1079

Location

United States

Related Subject Headings

  • Unfolded Protein Response
  • Stroke
  • Recovery of Function
  • Neuroprotection
  • Neurons
  • Neurology & Neurosurgery
  • Mice
  • Infarction, Middle Cerebral Artery
  • Gene Knock-In Techniques
  • Brain Infarction
 

Citation

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Yu, Z., Sheng, H., Liu, S., Zhao, S., Glembotski, C. C., Warner, D. S., … Yang, W. (2017). Activation of the ATF6 branch of the unfolded protein response in neurons improves stroke outcome. J Cereb Blood Flow Metab, 37(3), 1069–1079. https://doi.org/10.1177/0271678X16650218
Yu, Zhui, Huaxin Sheng, Shuai Liu, Shengli Zhao, Christopher C. Glembotski, David S. Warner, Wulf Paschen, and Wei Yang. “Activation of the ATF6 branch of the unfolded protein response in neurons improves stroke outcome.J Cereb Blood Flow Metab 37, no. 3 (March 2017): 1069–79. https://doi.org/10.1177/0271678X16650218.
Yu Z, Sheng H, Liu S, Zhao S, Glembotski CC, Warner DS, et al. Activation of the ATF6 branch of the unfolded protein response in neurons improves stroke outcome. J Cereb Blood Flow Metab. 2017 Mar;37(3):1069–79.
Yu, Zhui, et al. “Activation of the ATF6 branch of the unfolded protein response in neurons improves stroke outcome.J Cereb Blood Flow Metab, vol. 37, no. 3, Mar. 2017, pp. 1069–79. Pubmed, doi:10.1177/0271678X16650218.
Yu Z, Sheng H, Liu S, Zhao S, Glembotski CC, Warner DS, Paschen W, Yang W. Activation of the ATF6 branch of the unfolded protein response in neurons improves stroke outcome. J Cereb Blood Flow Metab. 2017 Mar;37(3):1069–1079.
Journal cover image

Published In

J Cereb Blood Flow Metab

DOI

EISSN

1559-7016

Publication Date

March 2017

Volume

37

Issue

3

Start / End Page

1069 / 1079

Location

United States

Related Subject Headings

  • Unfolded Protein Response
  • Stroke
  • Recovery of Function
  • Neuroprotection
  • Neurons
  • Neurology & Neurosurgery
  • Mice
  • Infarction, Middle Cerebral Artery
  • Gene Knock-In Techniques
  • Brain Infarction