Six α-synuclein (aSyn) point mutations are currently known to be associated with familial parkinsonism: A30P, E46K, H50Q, G51D, A53E, and A53T. We performed a comprehensive in vitro analysis to study the impact of all aSyn mutations on lipid binding and aggregation behavior. Markedly reduced lipid binding of A30P, moderately attenuated binding of G51D, and only very slightly reduced binding for the other mutants were observed. A30P was particularly prone to form metal ion induced oligomers, whereas A53T exhibited only weak tendencies to form oligomers. In turn, fibril formation occurred rapidly in H50Q, G51D, and A53T, but only slowly in A30P, suggesting mutants prone to form oligomers tend to form fibrils to a lesser extent. This was supported by the observation that fibril formation of wild type aSyn, A30P, and A53T was impaired in the presence of ferric iron. Additionally, we found the aggregation kinetics of mixtures of A30P or A53T and wt aSyn to be determined by the faster aggregating aSyn variant. Our results implicate differential mechanisms playing a role in aSyn pathology on the molecular level. This might contribute to a better understanding of Parkinson’s disease pathogenesis and provide potential links to develop prevention strategies and disease-modifying therapy.

中文翻译：

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α-突触核蛋白突变体对脂质结合和聚集的单分子荧光光谱和基于ThT荧光的检测方法的不同影响

目前已知六个α-突触核蛋白（aSyn）点突变与家族性帕金森病有关：A30P，E46K，H50Q，G51D，A53E和A53T。我们进行了全面的体外分析，以研究所有aSyn突变对脂质结合和聚集行为的影响。观察到A30P的脂质结合显着降低，G51D的结合适度减弱，而其他突变体的结合仅非常轻微地降低。A30P特别易于形成金属离子诱导的低聚物，而A53T仅表现出形成低聚物的弱趋势。反过来，原纤维形成在H50Q，G51D和A53T中迅速发生，而在A30P中仅缓慢发生，这表明易于形成寡聚物的突变体倾向于形成原纤维的程度较小。有人发现野生型aSyn，A30P，在铁水存在下，A53T受损。此外，我们发现A30P或A53T与wt aSyn的混合物的聚集动力学将由更快聚集的aSyn变体确定。我们的结果暗示在分子水平上差异机制在aSyn病理学中发挥作用。这可能有助于更好地了解帕金森氏病的发病机理，并为制定预防策略和疾病缓解疗法提供潜在的联系。