Upstream eventOxidative Stress in Brain
Unfolded Prortein Response
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|CYP2E1 activation and formation of protein adducts leading to neurodegeneration||adjacent||Moderate||Moderate|
Life Stage Applicability
Key Event Relationship Description
With the increasing ROS concentration and the accumulation of unfolded proteins an UPR is triggered in the ER. This is a defence mechanism in a cell, which starts with ER stress when there is an overload of ROS. At low level the activation of PERK in the UPR can prevent further oxidative stress. In several neurodegenerative diseases ER stress was reported. The exact mechanism and the link between ROS and UPR is not completely understood.
Evidence Supporting this KER
Several studies are performed to link oxidative stress with the UPR. Hayashi et al. showed that ROS, and specifically superoxide, plays a role in inducing ER stress by the UPR. Overexpression of SOD1, an antioxidant, reduces the induction of ATF-4 and CHOP, which are proteins released during UPR. Measurement were performed during ischemic brain injury. Chen et al. looked at the effect of ethanol on ER stress in neuron cells. Ethanol induces ROS formation by CYP2E1 activation, when antioxidant N-acetyl-L-cysteine (NAC) or GSH scavenged the production of ROS there an elimination of the expression of ER markers. Another possibility of ROS generating UPR is the interference of ROS with the folding of proteins in the ER. ROS can stimulate unfolded proteins to transform into misfolding proteins, or inactivate PDI/ERO1 which are responsible for the oxidation of unfolded proteins. Research on steatosis in the liver cells by Tsedensodnom et al. showed that after only after 2 hours of ethanol exposure a UPR response already can be measured. mRNAs levels of Bip, grp94 and dnajc3 were detected, which are known ER stress chaperones. Another pathway of inducing ER stress by UPR is that ROS can cause mitochondrial dysfunction. Cigarette smoke extract in retinal pigmented epithelial leads to accumulation of H2O2 in the mitochondria, which resulted in higher expression of UPR sensors.
There is a link between oxidative stress and the unfolded protein response, but the mechanism is not well understood.
Uncertainties and Inconsistencies
The UPR and ER stress can produce ROS by itself, so inducing a cell with a toxicant can also directly lead to ER stress. Time measurements are important to find out which event occurs first. Also the overall mechanism of this KER is not exactly known.
Quantitative Understanding of the Linkage
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Yang, F. & Luo, J. Endoplasmic reticulum stress and ethanol neurotoxicity. Biomolecules 5, 2538–2553 (2015).
Oakes, S. A. & Papa, F. R. The Role of Endoplasmic Reticulum Stress in Human Pathology. Annu. Rev. Pathol. Mech. Dis. 10, 173–194 (2015).
Ramirez-Alvarado, M., Kelly, J. W. & Dobson, C. M. Protein Misfolding Diseases: Current and Emerging Principles and Therapies. Protein Misfolding Diseases: Current and Emerging Principles and Therapies (2010). doi:10.1002/9780470572702
Hayashi, T. et al. Damage to the endoplasmic reticulum and activation of apoptotic machinery by oxidative stress in ischemic neurons. J. Cereb. Blood Flow Metab. 25, 41–53 (2005).
Chen, G. et al. Ethanol promotes endoplasmic reticulum stress-induced neuronal death: Involvement of oxidative stress. J. Neurosci. Res. 86, 937–946 (2008).
Tsedensodnom, O., Vacaru, A. M., Howarth, D. L., Yin, C. & Sadler, K. C. Ethanol metabolism and oxidative stress are required for unfolded protein response activation and steatosis in zebrafish with alcoholic liver disease. Dis. Model. Mech. 6, 1213–1226 (2013).
Cano, M. et al. Oxidative stress induces mitochondrial dysfunction and a protective unfolded protein response in RPE cells. Free Radic. Biol. Med. 69, 1–14 (2014).