A MAPK/c-Jun-mediated switch regulates the initial adaptive and cell death responses to mitochondrial damage in a neuronal cell model

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JournalThe International Journal of Biochemistry & Cell Biology
DateAccepted/In press - 17 Sep 2018
DateE-pub ahead of print - 17 Sep 2018
DatePublished (current) - Nov 2018
Number of pages14
Pages (from-to)73-86
Early online date17/09/18
Original languageEnglish


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 cJun can act in either a pro- or anti-apoptotic manner, depending on the level ofstress. 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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© 2018 Elsevier Ltd. This is an author-produced version of the published paper. Uploaded in accordance with the publisher’s self-archiving policy.

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