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Human Molecular Genetics Advance Access published online on September 6, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm249
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Paraquat induces dopaminergic dysfunction and proteasome impairment in DJ-1-deficient mice

Wonsuk Yang1,#, Linan Chen2,#, Yunmin Ding1, Xiaoxi Zhuang2 and Un Jung Kang1,*

1 Department of Neurology, The University of Chicago, Illinois 2 Department of Neurobiology, The University of Chicago, Illinois

* Corresponding author: Un Jung Kang, MD, Department of Neurology, The University of Chicago, 5841 South Maryland Avenue, Chicago, IL, 60637, USA. Email: unkang{at}uchicago.edu, Tel: 773-702-6389, Fax: 773-702-6538

Received July 19, 2007; Revised August 24, 2007; Accepted August 24, 2007

Parkinson's disease (PD) may be caused by a complex interaction of environmental insults and genetic susceptibilities. Previous studies of DJ-1-deficient mice have noted dopaminergic dysfunction mainly in older mice. To simulate the interaction of genetic factors and environmental factors, we treated DJ-1-deficient mice with paraquat. Even in relatively young mice, this combination produced dopamine loss and motor dysfunction. To determine the potential mechanism for the dopaminergic dysfunction, we investigated the proteasome function and ubiquitinated protein levels. DJ-1-deficient mice treated with paraquat showed decreased proteasome activities and increased ubiquitinated protein levels. To further investigate the mechanism of proteasome dysfunction, ATP levels and subunit protein levels of 19S ATPase Rpt6 and 20S ß5 were measured and noted to be decreased in the ventral midbrain, but not in the striatum. Finally, a transcription factor, Nrf2 that has been previously shown to be regulated by DJ-1 and to regulate 20S ß5 levels was decreased. These pathologies were not observed in brain regions of normal mice treated with paraquat. In conclusion, this study raises the possibility that environmental and genetic factors might cooperatively involve the mechanisms underlying proteasome impairment in PD brains.

# Both authors contributed to this paper equally.


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