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

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.

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Citation

Published Version (Please cite this version)

10.1177/0271678x16650218

Publication Info

Yu, Zhui, Huaxin Sheng, Shuai Liu, Shengli Zhao, Christopher C Glembotski, David S Warner, Wulf Paschen, Wei Yang, et al. (2017). Activation of the ATF6 branch of the unfolded protein response in neurons improves stroke outcome. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism, 37(3). pp. 1069–1079. 10.1177/0271678x16650218 Retrieved from https://hdl.handle.net/10161/23259.

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Scholars@Duke

Sheng

Huaxin Sheng

Associate Professor in Anesthesiology

We have successfully developed various rodent models of brain and spinal cord injuries in our lab, such as focal cerebral ischemia, global cerebral ischemia, head trauma, subarachnoid hemorrhage, intracerebral hemorrhage, spinal cord ischemia and compression injury. We also established cardiac arrest and hemorrhagic shock models for studying multiple organ dysfunction.  Our current studies focus on two projects. One is to examine the efficacy of catalytic antioxidant in treating cerebral ischemia and the other is to examine the efficacy of post-conditioning on outcome of subarachnoid hemorrhage induced cognitive dysfunction.

Wulf Paschen

Professor in Anesthesiology

My research interests are understanding the mechanisms underlying induction of cell death induced by a severe form of cellular stress. I am particularly interested in the role of the endoplasmic reticulum in the pathological process induced by transient cerebral ischemia and culminating in neuronal cell death. This pathological process is associated with an irreversible suppression of protein synthese that limits the ability of cells to withstand ischemia-induced impairment of endoplasmic reticulum function. We are working on strategies to activate restoration of protein synthese by conditional gene expression. A new area of research interest is understanding the role of small ubiquitin-like modifier (SUMO) conjugation to target proteins in the fate of neurons exposed to transient interruption of blood supply. We found that SUMO conjugation is dramatically activated after ischemia. This process is particularly activated in neurons located at the border of infarcts where it induces translocation of SUMO conjugated proteins to the nucleus.


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