Ryan, TA, Roper, KM, Bond, J et al. (3 more authors) (2018) A MAPK/c-Jun-mediated switch regulates the initial adaptive and cell death responses to mitochondrial damage in a neuronal cell model. The International Journal of Biochemistry and Cell Biology, 104. pp. 73-86. ISSN 1357-2725
Abstract
Parkinson’s disease (PD) is defined by the progressive loss of dopaminergic neurons. Mitochondrial dysfunction and oxidative stress are associated with PD although it is not fully understood how neurons respond to these stresses. How adaptive and apoptotic neuronal stress response pathways are regulated and the thresholds at which they are activated remains ambiguous. Utilising SH-SY5Y neuroblastoma cells, we show that MAPK/AP-1 pathways are critical in regulating the response to mitochondrial uncoupling. Here we found the AP-1 transcription factor c-Jun can act in either a pro- or anti-apoptotic manner, depending on the level of stress. JNK-mediated cell death in differentiated cells only occurred once a threshold of stress was surpassed. We also identified a novel feedback loop between Parkin activity and the c-Jun response, suggesting defective mitophagy may initiate MAPK/c-Jun-mediated neuronal loss observed in PD. Our data supports the hypothesis that blocking cell death pathways upstream of c-Jun as a therapeutic target in PD may not be appropriate due to crossover of the pro- and anti-apoptotic responses. Boosting adaptive responses or targeting specific aspects of the neuronal death response may therefore represent more viable therapeutic strategies.
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Copyright, Publisher and Additional Information: | (c) 2018 Elsevier Ltd. All rights reserved. This is an author produced version of a paper published in The International Journal of Biochemistry and Cell Biology. Uploaded in accordance with the publisher's self-archiving policy. | ||||||||
Keywords: | Mitophagy, Oxidative Stress, MAPK, AP-1 transcription factors, Parkinson’s, SH-SY5Y. | ||||||||
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Institution: | The University of Leeds | ||||||||
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > Institute of Molecular Medicine (LIMM) (Leeds) > Section of Opthalmology and Neurosciences (Leeds) | ||||||||
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Depositing User: | Symplectic Publications | ||||||||
Date Deposited: | 28 Sep 2018 10:47 | ||||||||
Last Modified: | 17 Sep 2019 00:38 | ||||||||
Status: | Published | ||||||||
Publisher: | Elsevier | ||||||||
Identification Number: | https://doi.org/10.1016/j.biocel.2018.09.008 |
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Filename: Ryan et al 2018 1-s2.0-S1357272518302012-main.pdf
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