Differential effects of Cu2+ and Fe3+ ions on in vitro amyloid formation of biologically-relevant α-synuclein variants.

Abstract

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.

• Authors: Emma Lorentzon, Ranjeet Kumar, Istvan Horvath, Pernilla Wittung-Stafshede
• Journal: Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine (Biometals) Vol. 33 Issue 2-3 Pg. 97-106 (06 2020) ISSN: 1572-8773 [Electronic] Netherlands
• PMID: 32170541 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid
• Ferric Compounds
• Protein Aggregates
• alpha-Synuclein
• Copper

Topics

• Amyloid (biosynthesis, metabolism)
• Copper (chemistry, pharmacology)
• Dose-Response Relationship, Drug
• Ferric Compounds (chemistry, pharmacology)
• Humans
• Parkinson Disease (drug therapy, metabolism)
• Protein Aggregates (drug effects)
• Protein Aggregation, Pathological (chemically induced, metabolism)
• Protein Conformation
• alpha-Synuclein (genetics, metabolism)