Low doses of the organic insecticide spinosad trigger lysosomal defects, ROS driven lipid dysregulation and neurodegeneration in flies

The plight of insect populations around the world and the threats it poses to agriculture and ecosystems has thrown insecticide use into the spotlight. Spinosad is an organic insecticide, considered less harmful to beneficial insects than synthetic insecticides, but its mode of action remains unclear. Using Drosophila, we show that low doses of spinosad reduce cholinergic response in neurons by antagonizing Dα6 nAChRs. Dα6 nAChRs are transported to lysosomes that become enlarged and accumulate upon spinosad treatment. Oxidative stress is initiated in the central nervous system, and spreads to midgut and disturbs lipid storage in metabolic tissues in a Dα6-dependent manner. Spinosad toxicity was ameliorated with the antioxidant N-Acetylcysteine amide (NACA). Chronic exposures lead to mitochondrial defects, severe neurodegeneration and blindness in adult animals. The many deleterious effects of low doses of this insecticide reported here point to an urgent need for rigorous investigation of its impacts on beneficial insects.