Modeling neurodegenerative diseases in Drosophila is conditioned by stress resistance and gut microbiome composition of the reference line

Drosophila is widely used to study the pathological mechanisms of human diseases in vivo, including metabolic and neurological disorders. In these models, disease-induced alterations in locomotion and stress resistance are generally monitored in comparison to healthy control flies, such the white-eyed strain w1118, used as a reference for normal physiology and behavior. Here we compared two independent w1118 lines and found that they differed strikingly in their susceptibility to oxidative stress and nutrient starvation, and less markedly in their locomotor performance. Interestingly, modulating the gut microbiome by rearing these flies under axenic conditions increased oxidative stress resistance of the more susceptible, but not the more resistant line, while it had no effect on starvation resistance for both lines. We also found that the stress-sensitive line had higher levels of Clostridiales bacteria and of the intracellular endosymbiont Wolbachia in the gut microbiota, as well as lower expression levels of immune effectors (antimicrobial peptides and lysozymes) in the head and gut. Both lines nevertheless showed similar susceptibility to pathogenic bacterial infections. In a transgenic Parkinsons disease model, the stress-resistant background strongly attenuated the progressive locomotor defects induced by pan-neuronal expression of human mutant -synuclein, but intriguingly not when -synuclein expression was restricted to a subset of brain dopaminergic neurons in the protocerebral anterior medial (PAM) cluster. These results suggest that taking into account unapparent features of the reference lines could improve the reproducibility and consistency of neurodegenerative disease models in Drosophila.