WR DTP project: Uncovering the phospho-regulation of responses to reactive oxygen species in neurons

Neurons in the brain are highly metabolically active and produce damaging reactive oxygen species (ROS) when at rest and when highly active. The build-up of cellular damage by neuronal ROS is thought to contribute to cognitive decline with age. However, ROS are not just deleterious, they provide an important signal for synapse function in a range of important processes, such as memory formation. How do neurons distinguish and respond appropriately to beneficial or toxic levels of ROS? We have recently found that low and high levels of ROS differentially activate two alternative kinase signalling pathways that subsequently alter the protein subunit composition of the transcription factor AP-1. We hypothesise that this occurs through differential phosphorylation of the AP-1 subunits. Using the fruit fly (Drosophila), which has fewer potential AP-1 subunit genes and phosphorylation sites, the student will determine the kinase signalling that drives AP-1 composition under low and high levels of ROS. We have also developed a co-expression system allowing production of soluble recombinant AP-1 heterodimers (this is a first) for in vitro validation of our in vivo findings. Finally we will use genomic analyses to ascertain how differential AP-1 phosphorylation and composition alters the transcriptional targets of AP-1 in neurons.

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