Journal Article

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

Wonsuk Yang, Linan Chen, Yunmin Ding, Xiaoxi Zhuang and Un Jung Kang

in Human Molecular Genetics

Volume 16, issue 23, pages 2900-2910
Published in print December 2007 | ISSN: 0964-6906
Published online September 2007 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddm249
Paraquat induces dopaminergic dysfunction and proteasome impairment in DJ-1-deficient mice

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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 β5 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 β5 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.

Journal Article.  5730 words.  Illustrated.

Subjects: Genetics and Genomics

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