The herbicide paraquat causes up-regulation and aggregation of α-synuclein in mice: Paraquat and α-synuclein

Abstract

α-Synuclein-containing aggregates represent a feature of a variety of neurodegenerative disorders, including Parkinson's disease (PD). However, mechanisms that promote intraneuronal α-synuclein assembly remain poorly understood. Because pesticides, particularly the herbicide paraquat, have been suggested to play a role as PD risk factors, the hypothesis that interactions between α-synuclein and these environmental agents may contribute to aggregate formation was tested in this study. Paraquat markedly accelerated the in vitro rate of α-synuclein fibril formation in a dose-dependent fashion. When mice were exposed to the herbicide, brain levels of α-synuclein were significantly increased. This up-regulation followed a consistent pattern, with higher α-synuclein at 2 days after each of three weekly paraquat injections and with protein levels returning to control values by day 7 post-treatment. Paraquat exposure was also accompanied by aggregate formation. Thioflavine S-positive structures accumulated within neurons of the substantia nigra pars compacta, and dual labeling and confocal imaging confirmed that these aggregates contained α-synuclein. The results suggest that up-regulation of α-synuclein as a consequence of toxicant insult and direct interactions between the protein and environmental agents are potential mechanisms leading to α-synuclein pathology in neurodegenerative disorders.