Modulation of neuronal function and redox homeostasis by Sulfiredoxin-1

Neurons are metabolically-demanding cells, producing reactive oxygen species (ROS) primarily as a by-product of aerobic respiration. ROS serve an important physiological role to modulate signalling pathways, gene expression, and cell function. However, unregulated levels of ROS can cause cellular damage and a state of oxidative stress (OS), which is a pathological hallmark of many neurodegenerative conditions. A better understanding of how ROS are controlled could elucidate therapeutic strategies for such conditions. My research sought to elucidate the physiological relevance of the antioxidant enzyme Sulfiredoxin-1 (Srx), which resolves Peroxiredoxins and additional putative substrates to maintain ROS homeostasis.

To investigate the role of Srx, I generated Drosophila melanogaster Srx mutants, which exhibited mild increases in sensitivity to OS. Redox-sensitive signalling pathways in Drosophila Srx mutants were differentially perturbed, and ROS levels in tissue homogenates were not significantly affected. These modest changes to redox homeostasis were contrasted by pronounced changes to fly behaviour and physiology, which include enhanced negative geotaxis responses and diminished neurotransmission in the visual system. Physiological changes to Drosophila Srx mutants were accompanied by enhanced neuron growth in vivo and in vitro, a morphological feature that is well-established to be regulated by redox signalling. Rat primary hippocampal neurons also exhibited enhanced growth following loss of Srx, demonstrating that Srx-regulated neuron growth is conserved across species.

Collectively, my work indicates that Srx modulates signalling pathways involved in neuronal growth and function, rather than conferring widespread defence against OS. My work has opened up avenues for further research into the identity of Srx-regulated signalling events and pathways and adds to a growing body of work that highlights ROS as being a critical modulators of nervous system development and function.