Abstract
BackgroundOxidative stress has been proposed to be involved in the pathogenesis of Parkinson's disease (PD). A plausible source of oxidative stress in nigral dopaminergic neurons is the redox reactions that specifically involve dopamine and produce various toxic molecules, i.e., free radicals and quinone species. α-Synuclein, a protein found in Lewy bodies characteristic of PD, is also thought to be involved in the pathogenesis of PD and point mutations and multiplications in the gene coding for α-synuclein have been found in familial forms of PD.ResultsWe used dopaminergic human neuroblastoma BE(2)-M17 cell lines stably transfected with WT or A30P mutant α-synuclein to characterize the effect of α-synuclein on dopamine toxicity. Cellular toxicity was analyzed by lactate dehydrogenase assay and by fluorescence-activated cell sorter analysis. Increased expression of either wild-type or mutant α-synuclein enhances the cellular toxicity induced by the accumulation of intracellular dopamine or DOPA.ConclusionsOur results suggest that an interplay between dopamine and α-synuclein can cause cell death in a neuron-like background. The data presented here are compatible with several models of cytotoxicity, including the formation of α-synuclein oligomers and impairment of the lysosomal degradation.
Highlights
Oxidative stress has been proposed to be involved in the pathogenesis of Parkinson’s disease (PD)
To study the relationship between a-synuclein and catecholamine toxicity, we used dopaminergic human neuroblastoma BE(2)-M17 cell lines stably transfected with WT or A30P mutant a-synuclein, as previously described [30]
In summary, we have shown that DA exposure increases the toxicity of the PD-related protein a-synuclein in dopaminergic neuroblastoma cell lines BE(2)-M17
Summary
Oxidative stress has been proposed to be involved in the pathogenesis of Parkinson’s disease (PD). Redox reactions that involve dopamine (DA) are a possible source of oxidative stress accounting for the more pronounced degeneration of dopaminergic neurons in PD. The discovery of three different missense mutations in the SNCA gene that codes for the a -synuclein protein, found in rare familial forms of PD indicates that a-synuclein is a likely causal factor in the pathogenesis of PD [11,12,13]. Further supporting this contention, multiplications of the SNCA gene are causal for PD, suggesting that increasing the amount of protein is sufficient to trigger the disease [14]. A-synuclein could modulate intracellular DA handling through interactions with proteins that regulate DA synthesis and uptake, such as tyrosine hydroxylase [25], the aromatic amino acid decarboxylase [26] and plasma membrane dopamine transporter [27,28,29]
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