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Mol Neurobiol. Author manuscript; available in PMC 2017 Jan 1.
Published in final edited form as:
Mol Neurobiol. 2016 Jan; 53(1): 532–544.
Published online 2014 Dec 9. doi: 10.1007/s12035-014-9029-6
PMCID: PMC4461562
NIHMSID: NIHMS647418
PMID: 25482050
Crosstalk between endoplasmic reticulum stress, oxidative stress and autophagy: Potential therapeutic targets for acute CNS injuries
Venkata Prasuja Nakka,1,2 Phanithi Prakash-babu,2 and Raghu Vemuganti1,*
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Abstract
Endoplasmic reticulum (ER) stress induces a variety of neuronal cell death pathways that play a critical role in the pathophysiology of Stroke. ER stress occurs when unfolded/misfolded proteins accumulate and the folding capacity of ER chaperones exceeds the capacity of ER lumen to facilitate their disposal. As a consequence, a complex set of signaling pathways will be induced that transmit from ER to cytosol and nucleus to compensate damage and to restore the normal cellular homeostasis, collectively known as unfolded protein response (UPR). However, failure of UPR due to severe or prolonged stress leads to cell death. Following acute CNS injuries, chronic disturbances in protein folding and oxidative stress prolong ER stress leading to sustained ER dysfunction and neuronal cell death. While ER stress responses have been well studied after stroke, there is an emerging need to study the association of ER stress with other cell pathways that exacerbate neuronal death after an injury. In this review we summarize the current understanding of the role for ER stress in acute brain injuries, highlighting the diverse molecular mechanisms associated with ER stress and its relation to oxidative stress and autophagy. We also discussed the existing and developing therapeutic options aimed to reduce ER stress to protect the CNS after acute injuries.
Keywords: ER stress, Oxidative stress, Autophagy, crosstalk, acute CNS injury
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1. Introduction
Endoplasmic reticulum (ER) plays a role in many essential cellular processes that include maintenance of intracellular Ca2+ homeostasis, folding of the newly synthesized secretory and membranous proteins and post-translational modifications (1, 2). As ~30% of the newly synthesized proteins are rapidly degraded due to improper folding (3), any increase in protein translation leads to a potential buildup of misfolded/unfolded proteins that stresses the cell. If this is combined with perturbations in the ER microenvironment such as alterations in redox state, depletion of Ca2+ levels and failure of posttranslational modifications, cells will be further stressed. As a result, the protein folding capacity of ER will be compromised, resulting in further accumulation of misfolded/unfolded proteins leading to unfolded protein response (UPR) generally referred as ER stress (4). The major goals of UPR/ER stress are 1) to shutdown protein translation to reduce the newly synthesized protein load, 2) to induce ER chaperones that promote protein folding, and 3) to activate ubiquitylation and proteasomal degradation of the misfolded/unfolded proteins. However, if stress is severe and persistent, UPR signaling switches from pro-survival to pro-apoptotic. ER stress is associated with numerous pathophysiological conditions including diabetes, stroke, traumatic injury to CNS and many neurodegenerative disorders (5).
ER stress precipitates neuronal death by multiple synergistic mechanisms. A major mechanism is the disruption of Ca2+ homeostasis that plays an important role in neuronal function and survival (2). ER is the major store for cellular Ca2+ and disruption of ER-associated Ca2+ channels including ryanodine receptors (RyRs) due to energy failure after stroke releases intracellular Ca2+ that induces proteases and nucleases leading to necrotic cell death. Depletion of Ca2+ stores in ER, activation of ER-associated Ca2+ -ATPases and failure of endoplasmic reticulum oxidoreductin-1 alpha (ERO1a) leading to disrupted protein disulphide bond formation also decrease protein folding leading to further accumulation of unfolded proteins (2, 6–9). Furthermore, ER stress induces cell death pathways associated with autophagy and apoptosis (10). All the above pathways collaborate to precipitate the neuronal death due to ER stress following acute CNS injuries (Figure 1). Although, limited UPR/ER stress is needed to induce neuroprotective mechanisms, excess ER stress leads to cell death and the molecular mechanisms that facilitate the switch from protection to death are yet to be understood completely. This review will discuss the current understanding of the complex signaling events induced by ER stress, highlighting the roles of ER stress in the pathophysiology of acute CNS injuries and emerging therapeutic opportunities for drug discovery.
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