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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Yu, Z; Sheng, H; Liu, S; Zhao, S; Glembotski, CC; Warner, DS; Paschen, W; Yang, W

Published Date

  • March 2017

Published In

Volume / Issue

  • 37 / 3

Start / End Page

  • 1069 - 1079

PubMed ID

  • 27217380

Pubmed Central ID

  • PMC5363481

Electronic International Standard Serial Number (EISSN)

  • 1559-7016

Digital Object Identifier (DOI)

  • 10.1177/0271678X16650218


  • eng

Conference Location

  • United States