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

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.

SLC30A10: A novel manganese transporter

“…Note that in C. elegans, Mn specifically targets dopaminergic (DAergic) resulting in their neurodegeneration. 10 Using green fluorescent protein (GFP)-labeled DAergic neurons, we found that expression of WT-SLC30A10 prevented Mn-induced DAergic neurodegeneration while expression of the L89P mutant had no protective effect. 23 This phenotypic result was confirmed by basal slowing response, a behavior specifically mediated by DAergic neurons.…”

Metal Concentrations of River Water and Sediments in West Java, Indonesia

“…Although Mn is an essential trace element, excess uptake of it may result in some nerve disorders 144 (Benedetto et al 2010). Toxic metals such as Pb were scarcely observed in the water samples.…”

Manganese Neurotoxicity

“…Particularly, DAergic degenerations were observed after acute exposure to this metal (Benedetto et al 2010;Settivari et al 2009). Benedetto et al, making use of various genetic strains of C. elegans in conjunction with the fluorescent-tagging of different classes of neuron types, have demonstrated that Mn causes a dose-dependent and specific degeneration of DAergic neurons (Benedetto et al 2010). This effect was absent in GABAergic, serotonergic, or glutamatergic neurons.…”

“…Mn exposure in worms has been associated with morphological alterations, reduced longevity, oxidative stress, and behavioral alterations, such as decreased head trash and body-bend frequencies Benedetto et al 2010;Settivari et al 2009;Wang and Xing 2008). Particularly, DAergic degenerations were observed after acute exposure to this metal (Benedetto et al 2010;Settivari et al 2009).…”