Generation of Ferric Iron Links Oxidative Stress to α-Synuclein Oligomer Formation

Background: Synucleinopathies such as Parkinson's disease are characterized by the deposition of aggregated alpha-synuclein in affected brain areas. As genes involved in mitochondrial function, mitochondrial toxins, and age-related mitochondrial impairment have been implicated in Parkinson's disease pathogenesis, an increase in reactive oxygen species resulting from mitochondrial dysfunction has been speculated to induce alpha-synuclein aggregation. In vitro, pore-forming, SDS-resistant alpha-synuclein oligomers are formed in presence of ferric iron and may represent an important toxic particle species. Methodology/Principal findings: We investigated the interplay of reactive oxygen species, antioxidants and iron oxidation state in regard to alpha-synuclein aggregation using confocal single particle fluorescence spectroscopy, Phenanthroline spectrometry and thiobarbituric acid reactive substances assay. We found that the formation of alpha-synuclein oligomers in presence of Fe3+ is due to a direct interaction. In contrast, oxidizing agents and hydroxyl radicals generated in the Fenton reaction did not directly affect alpha-synuclein oligomerization. However, reactive oxygen species could enhance aggregation via oxidation of ferrous to ferric iron when iron ions were present. Conclusions/Significance: Our data thus indicate that oxidative stress affects alpha-synuclein aggregation via oxidation of iron to the ferric state. This provides a new perspective on the role of mitochondrial toxins and mitochondrial dysfunction in the pathogenesis of Parkinson's disease.