Human Molecular Genetics Advance Access originally published online on September 6, 2007
Human Molecular Genetics 2007 16(23):2900-2910; doi:10.1093/hmg/ddm249
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Paraquat induces dopaminergic dysfunction and proteasome impairment in DJ-1-deficient mice
1 Department of Neurology and 2 Department of Neurobiology, The University of Chicago, IL, USA
* To whom correspondence should be addressed at: Department of Neurology, The University of Chicago, 5841 South Maryland Avenue, Chicago, IL 60637, USA. Tel: +1 7737026389; Fax: +1 7737026538; Email: unkang{at}uchicago.edu
Received July 19, 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.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.