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

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

Research output: Contribution to journalArticlepeer-review

67 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1069-1079
Number of pages11
JournalJournal of Cerebral Blood Flow and Metabolism
Issue number3
StatePublished - Mar 1 2017
Externally publishedYes


  • Brain ischemia
  • endoplasmic reticulum stress
  • neuroprotection
  • transgenic mice
  • unfolded protein response

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine


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