Neurology Department, Ludwig-Maximilians-University Munich, Munich, Germany.
J Parkinsons Dis. 2011;1(2):205-16. doi: 10.3233/JPD-2011-11040.
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.
帕金森病等突触核蛋白病的特征是受影响大脑区域中聚集的α-突触核蛋白的沉积。由于涉及线粒体功能的基因、线粒体毒素和与年龄相关的线粒体损伤与帕金森病的发病机制有关，因此推测线粒体功能障碍导致的活性氧增加会诱导α-突触核蛋白聚集。在体外，在铁离子存在下会形成具有孔形成能力且耐 SDS 的α-突触核蛋白寡聚物，并且可能代表一种重要的毒性颗粒物质。
方法/主要发现：我们使用共焦单颗粒荧光光谱法、邻菲啰啉光谱法和硫代巴比妥酸反应性物质测定法，研究了活性氧、抗氧化剂和铁氧化态在α-突触核蛋白聚集方面的相互作用。我们发现，Fe³⁺存在下α-突触核蛋白寡聚物的形成是由于直接相互作用。相比之下，Fenton 反应中产生的氧化剂和羟基自由基不会直接影响α-突触核蛋白的寡聚化。但是，当存在铁离子时，活性氧可以通过将亚铁离子氧化为铁离子来增强聚集。
结论/意义：因此，我们的数据表明，氧化应激通过将铁氧化为三价铁状态来影响α-突触核蛋白的聚集。这为线粒体毒素和线粒体功能障碍在帕金森病发病机制中的作用提供了新的视角。
