This thesis will summarise my work conducted on the study of Parkinson’s Disease in the model organism Drosophila melanogaster. The thesis is subdivided into four chapters with the first describing the contributions to the establishement of the dFOXO loss-of-function mutant as a model of sporadic Parkinson’s Disease (Tas et al., 2018). Additional unpublished results include the discovery and description of the shared downstream targets of dFOXO and the Fer2, a hypomorph mutant Parkinson’s Disease model also established in the lab of Emi Nagoshi (Bou Dib et al., 2014). The second chapter details a screen performed on the direct targets of Fer2, which was subsequently included in the publication of Miozzo et al. (2022). The third chapter describes the attempt at elucidating which dopaminergic neurons within D. melanogaster are most susceptible to Parkinson’s Disease associated genetic insults. It was found that dopaminergic neurons projecting to the β‘2 subdomain of the mushroom body showed selective vulnerability to mutant LrrkI1915T expression. The final chapter contains the observation of an age-dependent accumulation of melanic pigments on the surface of Drosophila central nervous system. It was found that the dFOXO downstream target yellow-f2, a dopachrome conversion enzyme, as well as pro-phenoloxidases were required for the creation of the head melanic aggregates. The knockdown by RNAi of yellow-f2 in a subset of dopaminergic neurons decreased the observed suddent accumulation of head melanic aggregates following a H2O2 stress, and resulted in increased survival. This effect was only observed in older flies, while younger flies did not show either an increase in aggregates or mortality following H2O2 feeding. The knockdown of yellow-f2 also abolished the age-dependent loss of dopaminergic neurons. Unlike for the survival phenotype, the neuroprotective effect of yellow-f2 knockdown was independent of head melanic aggregates. The observation that immune cells were more prevalent in the areas of increased head melanic aggregates, in combination with the already known role of melanization, suggested involvement of the immune system. An RNAseq performed on yellow-f2 knockdown flies as compared to control yielded differential expressed a number of genes including the IMD immune pathway inhibitor Diedel and the stress response Turandots. Comparison between the same genotypes but after H2O2 administration enriched transcripts for oxidoreductases, indicating that the absence of yellow-f2 allowed for a better response oxidative stress. These data suggest an involvement of age-dependent immune dysfunction, known as immunosenescence, in the survival response of the organism and dopaminergic neurons.