Master of Science
ATF4 is a transcription factor that is activated in response to integrated stress response (ISR). In neurons specifically, ATF4 has been suggested to act as a pro-apoptotic transcription factor. The expression of ATF4, as well as its downstream gene targets have been implicated in both in vivo and in vitro models of Alzheimer’s and Parkinson’s Disease. However, the mechanism by which ATF4 promotes cell death remains unclear. It was previously shown that overexpression of ATF4 in primary cortical neurons caused a reduction in glutathione levels, resulting in oxidative stress-induced cell death. The aim of this project was to investigate whether endogenous upregulation of ATF4 during ER-stress-induced activation of the ISR affects GSH levels and neuronal survival, and to identify factors that might mediate this response. Our results showed that in the presence of ER stress, WT cells possibly degrade GSH more rapidly compared to ATF4-deficient neurons, however, they compensate for this by increasing the rate of GSH de novo synthesis and maintain higher levels of GSH. Our findings also showed that the ATF4-dependent cell death observed in TG treated neurons is not induced by oxidative stress and cannot be ameliorated by the addition of antioxidants. Finally, we suggest that the underlying reason behind our differential observation regarding GSH consumption in overexpression and endogenous ISR activation pathways, is due to context dependent induction of different ATF4 target genes.
Mirshafiei, Fatemeh, "Investigating the role of endogenous ATF4 upregulation on neuronal glutathione level" (2018). Electronic Thesis and Dissertation Repository. 5974.