Abstract
Parkinson’s disease (PD) is a slowly progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons. Dopamine is a highly toxic compound leading to generation of reactive oxygen species (ROS). DJ-1 mutations lead to early-onset inherited PD. Here, we show that DJ-1 protects against dopamine toxicity. Dopamine-exposure led to upregulation of DJ-1. Overexpression of DJ-1 increased cell resistance to dopamine toxicity and reduced intracellular ROS. Contrary effects were achieved when DJ-1 levels were reduced by siRNA. Similarly, in vivo striatal administration of 6-hydroxydopamine led to upregulation of DJ-1. Upregulation of DJ-1 was mediated by the MAP kinases pathway through activation of ERK 1, 2 in vitro and in vivo. Hence, oxidative stress, generated by free cytoplasmic dopamine, leads to upregulation of DJ-1 through the MAP kinases pathway. This mechanism elucidates how mutations in DJ-1 prompt PD and imply that modulation of DJ-1 may serve as a novel neuroprotective modality.
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Acknowledgments
We would like to thank Mrs. Sara Dominitz for her help in preparing this manuscript. Supported by the Norma and Alan Aufzien Chair for PD Research, the Colton Foundation, and the Herzog Institute for the research of aging, Tel Aviv University; and by the National Parkinson Foundation, USA.
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Lev, N., Ickowicz, D., Barhum, Y. et al. DJ-1 protects against dopamine toxicity. J Neural Transm 116, 151–160 (2009). https://doi.org/10.1007/s00702-008-0134-4
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DOI: https://doi.org/10.1007/s00702-008-0134-4