Local Ionic Conditions Modulate the Aggregation Propensity and Influence the Structural Polymorphism of α-Synuclein

Area of Science:

• Biochemistry
• Neuroscience
• Structural Biology

Background:

• Parkinson's disease (PD) is characterized by alpha-synuclein (aSyn) aggregation.
• The exact triggers and mechanisms of aSyn aggregation are not fully understood.
• Local environmental factors, including ion concentrations, may influence aSyn aggregation.

Purpose of the Study:

• To investigate the impact of physiologically relevant ions (Ca2+ and Na+) on aSyn aggregation.
• To explore how these ions affect aSyn monomer structure, dynamics, and fibril polymorphism.

Main Methods:

• Thioflavin T (ThT) fluorescence assays for aggregation kinetics.
• Nuclear Magnetic Resonance (NMR) spectroscopy (1H-15N HSQC) for structural dynamics.
• Small-angle neutron scattering (SANS) and hydrogen-deuterium exchange mass spectrometry (HDX-MS) for structural changes.
• Molecular dynamics (MD) simulations for atomic-level insights.
• Atomic force microscopy (AFM) for fibril morphology.

Main Results:

• All tested ions accelerated aSyn aggregation, with Ca2+ showing the most potent effect.
• Ca2+ binds to the C-terminus, while Na+ interacts non-specifically.
• Na+ promotes extended aSyn structures, Ca2+ induces moderate extension and alters solvent dynamics.
• Distinct fibril polymorphs were observed under different ionic conditions.

Conclusions:

• The local ionic environment significantly influences aSyn structure, dynamics, and aggregation propensity.
• Ion-induced conformational changes and altered solvent interactions contribute to aSyn aggregation.
• Findings provide molecular insights into PD pathogenesis and potential therapeutic targets.