Synergistic effects on dopamine cell death in a Drosophila model of chronic toxin exposure

• We report a Drosophila model of chronic pesticide exposure relevant to Parkinson's disease (PD).
• We have used this model to demonstrate a neurotoxic interaction between: (1) paraquat and maneb, and (2) between maneb and inhibition of ubiquitin E1 ligase.
• These interactions may be relevant to pathophysiologic mechanisms of PD that involve multiple neurotoxic insults.

The neurodegenerative effects of Parkinson's disease (PD) are marked by a selective loss of dopaminergic (DA) neurons. Epidemiological studies suggest that chronic exposure to the pesticide paraquat may increase the risk for PD and DA cell loss. However, combined exposure with additional fungicide(s) including maneb and/or ziram may be required for pathogenesis. To explore potential pathogenic mechanisms, we have developed a Drosophila model of chronic paraquat exposure. We find that while chronic paraquat exposure alone decreased organismal survival and motor function, combined chronic exposure to both paraquat and maneb was required for DA cell death in the fly. To initiate mechanistic studies of this interaction, we used additional genetic reagents to target the ubiquitin proteasome system, which has been implicated in some rare familial forms of PD and the toxic effects of ziram. Genetic inhibition of E1 ubiquitin ligase, but not the proteasome itself, increased DA cell death in combination with maneb but not paraquat. These studies establish a model for long-term exposure to multiple pesticides, and support the idea that pesticide interactions relevant to PD may involve inhibition of protein ubiquitination.