Extracellular dopamine potentiates Mn-induced oxidative stress, lifespan reduction, and dopaminergic neurodegeneration in a BLI-3-dependent manner in caenorhabditis elegans

Alexandre Benedetto, Catherine Au, Daiana Silva Avila, Dejan Milatovic, Michael Aschner

Research output: Contribution to journalArticle

97 Citations (Scopus)

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 Mninduced 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.

Original languageEnglish (US)
JournalPLoS Genetics
Volume6
Issue number8
DOIs
StatePublished - Aug 2010
Externally publishedYes

Fingerprint

Parkinson disease
Caenorhabditis elegans
Manganese
dopamine
manganese
Parkinson Disease
Dopamine
Oxidative Stress
oxidative stress
toxicity
Dopamine Plasma Membrane Transport Proteins
NADPH Oxidase
Poisons
Dopaminergic Neurons
Environmental Exposure
disease occurrence
gene
Pesticides
Oxidants
Genes

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

Extracellular dopamine potentiates Mn-induced oxidative stress, lifespan reduction, and dopaminergic neurodegeneration in a BLI-3-dependent manner in caenorhabditis elegans. / Benedetto, Alexandre; Au, Catherine; Avila, Daiana Silva; Milatovic, Dejan; Aschner, Michael.

In: PLoS Genetics, Vol. 6, No. 8, 08.2010.

Research output: Contribution to journalArticle

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