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ToxSci Advance Access published online on October 3, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfl125
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received August 16, 2006
Accepted September 30, 2006

Original Article

Divergent Mechanisms of Paraquat, MPP+ and Rotenone Toxicity: Oxidation of Thioredoxin and Caspase-3 Activation

Sampath Ramachandiran 1, Jason M. Hansen 2, Dean P. Jones 3, Jason R. Richardson 4, and Gary W. Miller 1 *

1 Center for Neurodegenerative Disease, School of Medicine, Emory University, Atlanta, Georgia 30322; Department of Environmental and Occupational Health, Rollins School of Public Health, Emory University, Atlanta, Georgia 30322
2 Department of Pediatrics, Emory University, Atlanta, Georgia 30322
3 Department of Medicine and Clinical Biomarkers Laboratory, Emory University, Atlanta, Georgia 30322
4 Center for Neurodegenerative Disease, School of Medicine, Emory University, Atlanta, Georgia 30322; Department of Environmental and Occupational Health, Rollins School of Public Health, Emory University, Atlanta, Georgia 30322; Department of Environmental and Occupational Medicine, University of Medicine and Dentistry-New Jersey/ Robert Wood Johnson Medical School and Environmental and Occupational Health Sciences Institute, Piscataway, NJ 08854

* To whom correspondence should be addressed.
Gary W. Miller, E-mail: gary.miller{at}emory.edu


  Abstract

Paraquat, MPTP and rotenone have been shown to reproduce several features of Parkinson's disease (PD) in animal and cell culture models. Although these chemicals are known to perturb dopamine homeostasis and induce dopaminergic cell death, their molecular mechanisms of action are not well defined. We have previously shown that paraquat does not require functional dopamine transporter (DAT) and does not inhibit mitochondrial complex I in order to mediate its toxic action (Richardson et al., 2005). In this study we show that paraquat specifically oxidized the cytosolic form of thioredoxin (Trx1), activated Jun N-terminal kinase (JNK), followed by caspase-3 activation. Conversely, MPP+ and rotenone oxidized the mitochondrial form of thioredoxin (Trx2), but did not activate JNK-MAPK and caspase-3. Loading cells with exogenous dopamine did not exacerbate the toxicity of any of these compounds. These data suggest that, oxidative modification of cytosolic proteins is critical to paraquat toxicity, while oxidation of mitochondrial proteins is important for MPP+ and rotenone toxicity. In addition, intracellular dopamine does not seem to exacerbate the toxicity of these dopaminergic neurotoxicants in this model.

Keywords: Paraquat; MPTP; rotenone; cell death; thioredoxin; MAPK.
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