Activation of the ATF6 branch of the unfolded protein response in neurons improves stroke outcome.
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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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
Published In
DOI
EISSN
Publication Date
Volume
Issue
Start / End Page
Location
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