Kamper, Elisabeth Anna; (2025) Defence mechanisms against oxidative stress in the developing Drosophila central nervous system. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Neural stem cells (NSCs) are exposed to hypoxia and reactive oxygen species (ROS) during normal brain development. In mammals, this is further exacerbated if oxygen and nutrient supplies to the developing fetus are restricted, for example due to placental insufficiency. This compromises the growth of the fetus, yet in many cases the growth of the brain is selectively spared. The existence of this ‘brain sparing’ mechanism raises important questions about how neural stem cells cope with high levels of ROS and the damaging effects of oxidation of DNA, proteins and polyunsaturated fatty acids (PUFA) by ROS. Here, I address these questions using the powerful genetic model Drosophila. I establish dietary administration of reinforced (bis-allylic deuterated) linoleic acid as a new tool in Drosophila to inhibit PUFA peroxidation. I also generate targeted knockouts for a lipid peroxide repair enzyme, the Drosophila glutathione peroxidase homolog with thioredoxin peroxidase activity (Gtpx). Using a chemical oxidant exposure model, I revisit previous work showing that glial lipid droplet accumulation is required to protect NSC proliferation and find that this effect is context dependent and likely influenced by dietary lipid composition. I also investigate the role of the lipid peroxide repair enzyme Gtpx and find that it is specifically required for the maintenance of NSC proliferation during oxidative stress but not normal development. In glia, Gtpx is required for the proliferation, but not the survival, of NSCs. However, in NSC lineages, Gtpx is required for both the proliferation and survival of the stem cell. Experiments using cell-type specific genetics, reinforced linoleic acid supplementation and live imaging demonstrate that during oxidative stress, Gtpx deficient NSCs are primarily lost by ferroptosis, and not apoptosis. Together, these findings identify an enzymatic mechanism protecting NSCs from oxidative stress and provide a clear example of lipid peroxidation-dependent cell death in Drosophila.

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