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Extracellular Dopamine Potentiates Mn-Induced Oxidative Stress, Lifespan Reduction, and Dopaminergic Neurodegeneration in a BLI-3-Dependent Manner in Caenorhabditis elegans

Benedetto, A; Au, C; Avila, DS; Milatovic, D; Aschner, M; (2010) Extracellular Dopamine Potentiates Mn-Induced Oxidative Stress, Lifespan Reduction, and Dopaminergic Neurodegeneration in a BLI-3-Dependent Manner in Caenorhabditis elegans. PLOS GENET , 6 (8) , Article e1001084. 10.1371/journal.pgen.1001084. Green open access

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Abstract

Parkinson's disease (PD)-mimicking drugs and pesticides, and more recently PD-associated gene mutations, have been studied in cell cultures and mammalian models to decipher the molecular basis of PD. Thus far, a dozen of genes have been identified that are responsible for inherited PD. However they only account for about 8% of PD cases, most of the cases likely involving environmental contributions. Environmental manganese (Mn) exposure represents an established risk factor for PD occurrence, and both PD and Mn-intoxicated patients display a characteristic extrapyramidal syndrome primarily involving dopaminergic (DAergic) neurodegeneration with shared common molecular mechanisms. To better understand the specificity of DAergic neurodegeneration, we studied Mn toxicity in vivo in Caenorhabditis elegans. Combining genetics and biochemical assays, we established that extracellular, and not intracellular, dopamine (DA) is responsible for Mn-induced DAergic neurodegeneration and that this process (1) requires functional DA-reuptake transporter (DAT-1) and (2) is associated with oxidative stress and lifespan reduction. Overexpression of the anti-oxidant transcription factor, SKN-1, affords protection against Mn toxicity, while the DA-dependency of Mn toxicity requires the NADPH dual-oxidase BLI-3. These results suggest that in vivo BLI-3 activity promotes the conversion of extracellular DA into toxic reactive species, which, in turn, can be taken up by DAT-1 in DAergic neurons, thus leading to oxidative stress and cell degeneration.

Type: Article
Title: Extracellular Dopamine Potentiates Mn-Induced Oxidative Stress, Lifespan Reduction, and Dopaminergic Neurodegeneration in a BLI-3-Dependent Manner in Caenorhabditis elegans
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.pgen.1001084
Publisher version: http://dx.doi.org/10.1371/journal.pgen.1001084
Language: English
Additional information: © 2010 Benedetto et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by NIH R01 ES10563 to MA. The funders had no role in study design, data collection andanalysis, decision to publish, or preparation of the manuscript.
Keywords: RAT SUBSTANTIA-NIGRA, MANGANESE-INDUCED PARKINSONISM, ONE-ELECTRON REDUCTION, HUMAN ALPHA-SYNUCLEIN, DUAL OXIDASE BLI-3, SUPEROXIDE-DISMUTASE, IDIOPATHIC PARKINSONISM, C.-ELEGANS, CELL-DEATH, INDUCED DEGENERATION
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
URI: https://discovery.ucl.ac.uk/id/eprint/168182
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