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Differential effects of Cu2+ and Fe3+ ions on in vitro amyloid formation of biologically-relevant α-synuclein variants.
Biometals ( IF 4.1 ) Pub Date : 2020-03-13 , DOI: 10.1007/s10534-020-00234-4
Emma Lorentzon 1, 2 , Ranjeet Kumar 1 , Istvan Horvath 1 , Pernilla Wittung-Stafshede 1
Affiliation  

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.



中文翻译:

Cu2 +和Fe3 +离子对生物学相关的α-突触核蛋白变体的体外淀粉样蛋白形成的差异作用。

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。

更新日期:2020-04-20
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