Alterations in metal ion homeostasis appear coupled to neurodegenerative disorders but mechanisms are unknown. Amyloid formation of the protein α-synuclein in brain cells is a hallmark of Parkinson’s disease. α-Synuclein can bind several metal ions in vitro and such interactions may affect the assembly process. Here we used biophysical methods to study the effects of micromolar concentrations of Cu²⁺ and Fe³⁺ ions on amyloid formation of selected α-synuclein variants (wild-type and A53T α-synuclein, in normal and N-terminally acetylated forms). As shown previously, Cu²⁺ speeds up aggregation of normal wild-type α-synuclein, but not the acetylated form. However, Cu²⁺ has a minimal effect on (the faster) aggregation of normal A53T α-synuclein, despite that Cu²⁺ binds to this variant. Like Cu²⁺, Fe³⁺ speeds up aggregation of non-acetylated wild-type α-synuclein, but with acetylation, Fe³⁺ instead slows down aggregation. In contrast, for A53T α-synuclein, regardless of acetylation, Fe³⁺ slows down aggregation with the effect being most dramatic for acetylated A53T α-synuclein. The results presented here suggest a correlation between metal-ion modulation effect and intrinsic aggregation speed of the various α-synuclein variants.

金属离子稳态的改变似乎与神经退行性疾病有关，但机制尚不清楚。脑细胞中蛋白质α-突触核蛋白的淀粉样蛋白形成是帕金森氏病的标志。α-突触核蛋白可以在体外结合多种金属离子，这种相互作用可能会影响组装过程。在这里，我们使用生物物理方法研究了微摩尔浓度的Cu ²⁺和Fe ³⁺离子对所选α-突触核蛋白变体（正常和N端乙酰化形式的野生型和A53Tα-突触核蛋白）淀粉样蛋白形成的影响。如前所述，Cu ²⁺可以加速正常野生型α-突触核蛋白的聚集，但不能加速乙酰化形式。但是，Cu ²⁺尽管Cu ²⁺结合了该变体，但对正常A53Tα-突触核蛋白的聚集（更快）的影响最小。像Cu ²⁺一样，Fe ³⁺可以加速非乙酰化野生型α-突触核蛋白的聚集，但是通过乙酰化，Fe ^3+可以减慢聚集。相反，对于A53Tα-突触核蛋白，无论乙酰化如何，Fe ^3+都会减慢聚集，其中乙酰化A53Tα-突触核蛋白的作用最为明显。此处显示的结果表明，金属离子调制效应与各种α-突触核蛋白变体的固有聚集速度之间存在相关性。