The herbicide paraquat causes up-regulation and aggregation of alpha-synuclein in mice: paraquat and alpha-synuclein.
alpha-Synuclein-containing aggregates represent a feature of a variety of neurodegenerative disorders, including Parkinson's disease (PD). However, mechanisms that promote intraneuronal alpha-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 alpha-synuclein and these environmental agents may contribute to aggregate formation was tested in this study. Paraquat markedly accelerated the in vitro rate of alpha-synuclein fibril formation in a dose-dependent fashion. When mice were exposed to the herbicide, brain levels of alpha-synuclein were significantly increased. This up-regulation followed a consistent pattern, with higher alpha-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 alpha-synuclein. The results suggest that up-regulation of alpha-synuclein as a consequence of toxicant insult and direct interactions between the protein and environmental agents are potential mechanisms leading to alpha-synuclein pathology in neurodegenerative disorders.
Manning-Bog
Amy B
AB
Parkinson's Institute, Sunnyvale, California 94089, USA.
McCormack
Alison L
AL
Li
Jie
J
Uversky
Vladimir N
VN
Fink
Anthony L
AL
Di Monte
Donato A
DA
D000818:Animals; D006540:Herbicides / Q000494:pharmacology*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism*; D010269:Paraquat / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D051843:Synucleins; D015854:Up-Regulation / Q000187:drug effects*; D051844:alpha-Synuclein
D006540:Herbicides; D009419:Nerve Tissue Proteins; D011994:Recombinant Proteins; C497605:Snca protein, mouse; D051843:Synucleins; D051844:alpha-Synuclein; D010269:Paraquat