NMR of α-synuclein–polyamine complexes elucidates the mechanism and kinetics of induced aggregation

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Abstract
The aggregation of α‐synuclein is characteristic of Parkinson's disease (PD) and other neurodegenerative synucleinopathies. The 140‐aa protein is natively unstructured; thus, ligands binding to the monomeric form are of therapeutic interest. Biogenic polyamines promote the aggregation of α‐synuclein and may constitute endogenous agents modulating the pathogenesis of PD. We characterized the complexes of natural and synthetic polyamines with α‐synuclein by NMR and assigned the binding site to C‐terminal residues 109–140. Dissociation constants were derived from chemical shift perturbations. Greater polyamine charge (+2 → +5) correlated with increased affinity and enhancement of fibrillation, for which we propose a simple kinetic mechanism involving a dimeric nucleation center. According to the analysis, polyamines increase the extent of nucleation by ∼104 and the rate of monomer addition ∼40‐fold. Significant secondary structure is not induced in monomeric α‐synuclein by polyamines at 15°C. Instead, NMR reveals changes in a region (aa 22–93) far removed from the polyamine binding site and presumed to adopt the β‐sheet conformation characteristic of fibrillar α‐synuclein. We conclude that the C‐terminal domain acts as a regulator of α‐synuclein aggregation.