Differential effects of Cu and Fe ions on in vitro amyloid formation of biologically-relevant α-synuclein variants.

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.