Journal
BIOMETALS
Volume 33, Issue 2-3, Pages 97-106Publisher
SPRINGER
DOI: 10.1007/s10534-020-00234-4
Keywords
alpha-Synuclein; Parkinson's disease; Metal ions; Acetylation; Thioflavin T; Amyloid formation
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Funding
- Knut och Alice Wallenbergs Stiftelse [X] Funding Source: Medline
- Stiftelsen Olle Engkvist Byggmästare [X] Funding Source: Medline
- Vetenskapsrådet [X] Funding Source: Medline
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Alterations in metal ion homeostasis appear coupled to neurodegenerative disorders but mechanisms are unknown. Amyloid formation of the protein alpha-synuclein in brain cells is a hallmark of Parkinson's disease. alpha-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(2+)and Fe(3+)ions on amyloid formation of selected alpha-synuclein variants (wild-type and A53T alpha-synuclein, in normal and N-terminally acetylated forms). As shown previously, Cu(2+)speeds up aggregation of normal wild-type alpha-synuclein, but not the acetylated form. However, Cu(2+)has a minimal effect on (the faster) aggregation of normal A53T alpha-synuclein, despite that Cu(2+)binds to this variant. Like Cu2+, Fe(3+)speeds up aggregation of non-acetylated wild-type alpha-synuclein, but with acetylation, Fe(3+)instead slows down aggregation. In contrast, for A53T alpha-synuclein, regardless of acetylation, Fe(3+)slows down aggregation with the effect being most dramatic for acetylated A53T alpha-synuclein. The results presented here suggest a correlation between metal-ion modulation effect and intrinsic aggregation speed of the various alpha-synuclein variants.
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