Neurotoxicity of the Parkinson's Disease-Associated Pesticide Ziram Is Synuclein-Dependent in Zebrafish Embryos

Exposure to the commonly used dithiocarbamate (DTC) pesticide ziram is associated with an increased risk of developing Parkinson's disease (PD), although the mechanisms of toxicity are not completely understood. In this study, we utilized zebrafish (ZF) embryos to study the mechanisms of ziram's neurotoxicity in vivo. Nanomolar concentrations of ziram caused selective loss of dopaminergic (DA) neurons and impaired swimming behavior. Since ziram increases α-synuclein (α-syn) concentrations in rat primary neuronal cultures, we investigated the effect of ziram on ZF γ-synuclein 1 (γ1). ZF express 3 synuclein isoforms and ZF γ1 appears to be a functional homologue of α-syn. We found that recombinant ZF γ1 formed fibrils in vitro and overexpression of ZF γ1 in ZF embryos led to the formation of neuronal aggregates and neurotoxicity similarly to α-syn. Importantly, knockdown of ZF γ1 with morpholinos or disruption of oligomers with the molecular tweezer CLR01 prevented ziram's DA toxicity. These data demonstrate that ziram is selectively toxic to DA neurons in vivo and this toxicity is synuclein-dependent. These findings have important implications for understanding the mechanisms by which pesticides may cause PD.