TY - JOUR T1 - Extracellular Dopamine Potentiates Mn-Induced Oxidative Stress, Lifespan Reduction, and Dopaminergic Neurodegeneration in a BLI-3–Dependent Manner in Caenorhabditis elegans A1 - Benedetto, Alexandre A1 - Au, Catherine A1 - Avila, Daiana Silva A1 - Milatovic, Dejan A1 - Aschner, Michael Y1 - 2010/08/26 N2 - Author Summary In Parkinson's disease (PD), motor neurons that produce dopamine degenerate, leading to a characteristic syndrome including tremor, rigidity, and bradykinesia. The mechanisms leading to PD have been under intense investigation, identifying hereditary mutations responsible for about 8% of the cases. However, multiple environmental factors contribute to PD; and, amongst those, manganese (Mn) exposure from pesticides, industrial fumes, and gasoline additives has been robustly associated with PD. To gain insights into processes leading to the specific degeneration of dopaminergic neurons, we used a simple animal model, the nematode Caenorhabditis elegans, which, upon Mn exposure, recapitulates key molecular processes known to be involved in PD. Combining biochemistry and genetics, we demonstrate that dopamine secreted by the neurons and not intracellular dopamine is directly involved in the generation of toxic reactive oxygen species. We identify two essential mediators of this dopamine-dependent effect which are an extracellularly active enzyme called dual-oxidase and the dopamine re-uptake transporter. We also reveal that a transcription factor which is strongly expressed in two neurons involved in the regulation of aging is a powerful modulator of the dopamine-dependent toxicity. Our study establishes novel evidence of the link among PD, aging, and oxidative stress within the context of exposure to Mn. JF - PLOS Genetics JA - PLOS Genetics VL - 6 IS - 8 UR - https://doi.org/10.1371/journal.pgen.1001084 SP - e1001084 EP - PB - Public Library of Science M3 - doi:10.1371/journal.pgen.1001084 ER -