Chronic Exposure to Paraquat Induces Alpha-Synuclein Pathogenic Modifications in Drosophila

Parkinson's disease (PD) is characterized by the progressive accumulation of neuronal intracellular aggregates largely composed of alpha-Synuclein (alpha Syn) protein. The process of alpha Syn aggregation is induced during aging and enhanced by environmental stresses, such as the exposure to pesticides. Paraquat (PQ) is an herbicide which has been widely used in agriculture and associated with PD. PQ is known to cause an increased oxidative stress in exposed individuals but the consequences of such stress on alpha Syn conformation remains poorly understood. To study alpha Syn pathogenic modifications in response to PQ, we exposed Drosophila expressing human alpha Syn to a chronic PQ protocol. We first showed that PQ exposure and alpha Syn expression synergistically induced fly mortality. The exposure to PQ was also associated with increased levels of total and phosphorylated forms of alpha Syn in the Drosophila brain. Interestingly, PQ increased the detection of soluble alpha Syn in highly denaturating buffer but did not increase alpha Syn resistance to proteinase K digestion. These results suggest that PQ induces the accumulation of toxic soluble and misfolded forms of alpha Syn but that these toxic forms do not form fibrils or aggregates that are detected by the proteinase K assay. Collectively, our results demonstrate that Drosophila can be used to study the effect of PQ or other environmental neurotoxins on alpha Syn driven pathology.

Automated summary

Parkinson's disease is characterized by the accumulation of alpha-Synuclein in neuronal cells, induced by exposure to herbicide Paraquat. This exposure also leads to increased levels of alpha Syn in the brain of fruit flies and synergistically induces mortality. Furthermore, Paraquat causes the accumulation of toxic soluble and misfolded forms of alpha-Synuclein.