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Twists and turns (non-helical) on the transcriptional road to oxidative neuronal death: implications for brain protection and repair.
Oxidative stress has been implicated in almost every neurological condition, and yet antioxidants have been dismal failures in clinical trials. Over the past 25 years, our laboratory has investigated an in vitro model of oxidative death in neurons. This model system has revealed that disrupted oxidative homeostasis does not kill neurons via random destruction of macromolecules but rather via aberrant signaling leading to the activation of the transcriptional activator, ATF4, and induction of a casette of prodeath genes. Our path to this exciting new model of oxidative death has been formative but not linear and I will describe and discuss how serendipity and luck along with some rigorous experimentation have influenced our models and questions, and how future therapeutics targeted at abrogating oxidative death, now known as ferroptosis, may overcome past failures.
