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J. Biol. Chem., Vol. 277, Issue 3, 1641-1644, January 18, 2002

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ACCELERATED PUBLICATION
The Herbicide Paraquat Causes Up-regulation and Aggregation of -Synuclein in Mice
PARAQUAT AND -SYNUCLEIN^*

Amy B. Manning-Bog, Alison L. McCormack, Jie Li^§, Vladimir N. Uversky^§, Anthony L. Fink^§, and Donato A. Di Monte^¶

From the  Parkinson's Institute, Sunnyvale, California 94089 and the ^§ Department of Chemistry and Biochemistry, University of California, Santa Cruz, California 95064

-Synuclein-containing aggregates represent a feature of a variety of neurodegenerative disorders, including Parkinson's disease (PD). However, mechanisms that promote intraneuronal -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 -synuclein and these environmental agents may contribute to aggregate formation was tested in this study. Paraquat markedly accelerated the in vitro rate of -synuclein fibril formation in a dose-dependent fashion. When mice were exposed to the herbicide, brain levels of -synuclein were significantly increased. This up-regulation followed a consistent pattern, with higher -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 -synuclein. The results suggest that up-regulation of -synuclein as a consequence of toxicant insult and direct interactions between the protein and environmental agents are potential mechanisms leading to -synuclein pathology in neurodegenerative disorders.

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