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, h...

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Bibliographic Details
Published in:The Journal of biological chemistry 2002-01, Vol.277 (3), p.1641-1644
Main Authors: Manning-Bog, Amy B, McCormack, Alison L, Li, Jie, Uversky, Vladimir N, Fink, Anthony L, Di Monte, Donato A
Format: Article
Language:English
Subjects:
a-Synuclein
alpha-Synuclein
Animals
Herbicides - pharmacology
Mice
Nerve Tissue Proteins - chemistry
Nerve Tissue Proteins - metabolism
Paraquat - pharmacology
Recombinant Proteins - chemistry
Recombinant Proteins - metabolism
Synucleins
Up-Regulation - drug effects
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Summary: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.
ISSN:0021-9258
DOI:10.1074/jbc.C100560200