Abstract
Endoplasmic reticulum (ER) is the main organelle for protein synthesis, trafficking and maintaining intracellular Ca2+ homeostasis. The stress response of ER results from the disruption of ER homeostasis in neurological disorders. Among these disorders, cerebral ischemia is a prevalent reason of death and disability in the world. ER stress stemed from ischemic injury initiates unfolded protein response (UPR) regarded as a protection mechanism. Important, disruption of Ca2+ homeostasis resulted from cytosolic Ca2+ overload and depletion of Ca2+ in the lumen of the ER could be a trigger of ER stress and the misfolded protein synthesis. Brain cells including neurons, glial cells and endothelial cells are involved in the complex pathophysiology of ischemic stroke. This is generally important for protein underfolding, but even more for cytosolic Ca2+ overload. Mild ER stress promotes cells to break away from danger signals and enter the adaptive procedure with the activation of pro-survival mechanism to rescue ischemic injury, while chronic ER stress generally serves as a detrimental role on nerve cells via triggering diverse pro-apoptotic mechanism. What’s more, the determination of some proteins in UPR during cerebral ischemia to cell fate may have two diametrically opposed results which involves in a specialized set of inflammatory and apoptotic signaling pathways. A reasonable understanding and exploration of the underlying molecular mechanism related to ER stress and cerebral ischemia is a prerequisite for a major breakthrough in stroke treatment in the future. This review focuses on recent findings of the ER stress as well as the progress research of mechanism in ischemic stroke prognosis provide a new treatment idea for recovery of cerebral ischemia.
Highlights
Stroke is the second highest cause of death
This review aims to contribute to this growing area of research by summarizing the molecular pathways of Endoplasmic reticulum (ER) stress controlling cell fate after cerebral ischemia
The evidence for activation of pathways associated with ER stress after cerebral ischemia is strong and the life of brain cells cannot be separated from the unfolded protein response (UPR) propagated or induced by ER stress
Summary
Stroke is the second highest cause of death. Cerebral ischemia stemming from arterial occlusion is responsible for most of the stroke, a catastrophic illness leading to permanent disability in 80% of survivors (Moskowitz et al, 2010; Campbell et al, 2019; Jayaraj et al, 2019). In the face of such an intractable problem, relatively effective interventions to prevent death and improve brain cells recovery are in short supply today (Ekker et al, 2018; Zerna et al, 2018). Endoplasmic reticulum served as a highly multifaceted organelle essentially differs from the surrounding cytoplasm both structurally and functionally (Sanderson et al, 2015). Enzymes, and cofactors associated with ER regulate precise folding of newly synthesized proteins and assist polypeptides in achieving final functional conformation. Under the physiological environment, misfolded proteins are decreased and degraded by the accurate quality control mechanisms of proteasome, lysosome, and autophagy pathways to maintain the protein homeostasis called proteostasis in eukaryotic cells (Kaushik and Cuervo, 2015; Hetz and Saxena, 2017)
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