Affiliations: Neurology Department, Ludwig-Maximilians-University Munich, Munich, Germany | Center for Neuropathology und Prion Research, Ludwig-Maximilians-University Munich, Munich, Germany | Adolf Butenandt-Institut for Biochemistry, Ludwig-Maximilians-University, Munich, Munich, Germany
Note:  Correspondence to: Prof. Dr. Armin Giese, Zentrum für Neuropathologie, und Prionforschung, Feodor-Lynen-Str. 23, D- 81377 München, Germany. Tel.: +49 (0)89 2180 78048; Fax: +49 (0)89 2180 78037; E-mail: [email protected]
Abstract: Background: Synucleinopathies such as Parkinson's disease are characterized by the deposition of aggregated α-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 α-synuclein aggregation. In vitro, pore-forming, SDS-resistant α-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 α-synuclein aggregation using confocal single particle fluorescence spectroscopy, Phenanthroline spectrometry and thiobarbituric acid reactive substances assay. We found that the formation of α-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 α-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 α-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.
Keywords: Parkinson's disease, α-synuclein, iron, oxidative stress, protein aggregation, pesticides