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.
Highlights
Mn is the twelfth most prevalent natural element in the Earth’s crust [1] and is an essential transition metal required for normal growth, development and cellular homeostasis [2,3]
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 Parkinson’s disease (PD)
We demonstrate that dopamine secreted by the neurons and not intracellular dopamine is directly involved in the generation of toxic reactive oxygen species
Summary
Mn is the twelfth most prevalent natural element in the Earth’s crust [1] and is an essential transition metal required for normal growth, development and cellular homeostasis [2,3]. It acts as a cofactor for multiple enzymes (Mn superoxide dismutase, pyruvate carboxylase, arginase, and glutamine synthase) [4,5,6,7,8] and can substitute for magnesium (Mg) in many enzymatic reactions catalyzed by kinases. Mn is used in other industrial and agricultural applications Fungicides, such as Maneb or Mancozeb, increase the risk of environmental Mn exposure in agricultural workers [16]. An organic Mn compound, methylcyclopentadienyl Mn tricarbonyl (MMT), used as an octane booster or anti-knock agent in gasoline, has been shown to cause adverse health effects [17,18,19,20]
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