Human Molecular Genetics Advance Access published online on June 15, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh180
© 2004 by Oxford University Press
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1 Department of Physiology and Biophysics, State University of New York at Buffalo, Buffalo, NY 14214, USA
* To whom correspondence should be addressed. E-mail: jianfeng{at}buffalo.edu.
Parkinson's disease (PD) is characterized by the selective degeneration of dopaminergic (DA) neurons in substantia nigra pars compacta (SNpc). A combination of genetic and environmental factors contributes to such a specific loss. Among the five PD-linked genes identified so far, parkin, a protein-ubiquitin E3 ligase, appears to be the most prevalent genetic factor in PD. Although a variety of substrates have been identified for parkin, none of them is selectively expressed in nigral DA neurons. It remains unclear how accumulation of these substrates in the absence of functional parkin may cause the selective death of dopaminergic neurons in SNpc. Here we show that overexpression of parkin protected human dopaminergic neuroblastoma cell line (SH-SY5Y) against apoptosis induced by dopamine or 6-OHDA, but not by H2O2 or rotenone. Parkin significantly attenuated dopamine-induced activation of JNK and caspase-3. It also decreased the level of reactive oxygen species (ROS) and protein carbonyls in the cell. Inhibiting DA uptake through dopamine transporter or treating the cell with antioxidants significantly reduced oxidative stress and dopamine toxicity. Furthermore, PD-linked mutations of parkin significantly abrogated the protective effect of wild-type parkin, as well as its ability to suppress ROS and protein carbonylation. These results suggest that parkin protects against dopamine toxicity by decreasing oxidative stress and ensuing activation of apoptotic programs such as the JNK/Caspase pathway. This protective function of parkin, which is greatly attenuated by its PD-linked mutations, may be uniquely important for the survival of dopaminergic neurons, as they are constantly threatened by oxyradicals produced during dopamine oxidation.
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Parkin protects human dopaminergic neuroblastoma cells against dopamine-induced apoptosis
2 Department of Physiology and Biophysics, State University of New York at Buffalo, 124 Sherman Hall, Buffalo, NY 14214, USA
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