Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden.
Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden.
Biometals. 2020 Jun;33(2-3):97-106. doi: 10.1007/s10534-020-00234-4. Epub 2020 Mar 13.
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 Cu and Fe 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, Cu speeds up aggregation of normal wild-type α-synuclein, but not the acetylated form. However, Cu has a minimal effect on (the faster) aggregation of normal A53T α-synuclein, despite that Cu binds to this variant. Like Cu, Fe speeds up aggregation of non-acetylated wild-type α-synuclein, but with acetylation, Fe instead slows down aggregation. In contrast, for A53T α-synuclein, regardless of acetylation, Fe 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.
金属离子平衡的改变似乎与神经退行性疾病有关，但具体机制尚不清楚。脑细胞中蛋白质α-突触核蛋白的淀粉样形成是帕金森病的一个标志。α-突触核蛋白在体外可以结合几种金属离子，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 和 Fe 离子对选定的α-突触核蛋白变体（野生型和 A53T α-突触核蛋白，正常和 N 端乙酰化形式）淀粉样形成的影响。如前所述，Cu 加速了正常野生型α-突触核蛋白的聚集，但不能加速乙酰化形式的聚集。然而，尽管 Cu 与该变体结合，但 Cu 对正常 A53T α-突触核蛋白（聚集速度更快）的聚集影响很小。与 Cu 一样，Fe 加速了非乙酰化野生型α-突触核蛋白的聚集，但乙酰化后，Fe 反而会减缓聚集。相比之下，对于 A53T α-突触核蛋白，无论是否乙酰化，Fe 都会减缓聚集，乙酰化的 A53T α-突触核蛋白的效果最为显著。本研究结果表明，金属离子调节作用与各种α-突触核蛋白变体的固有聚集速度之间存在相关性。
