Brain metal dyshomeostasis and altered structural dynamics of the presynaptic protein α-synuclein (αS) are both implicated in the pathology of Parkinson’s disease (PD), yet a mechanistic understanding of disease progression in the context of αS structure and metal interactions remains elusive. Recently, we communicated the influence of iron, a prevalent redox-active brain biometal, on the aggregation propensity and secondary structure of N-terminally acetylated αS (NAcαS), the physiologically relevant form in humans. We further demonstrated that under aerobic conditions, Fe(II) commits NAcαS to a PD-relevant oligomeric assembly, as verified by the oligomer-selective A11 antibody, that does not have any parallel β-sheet character but contains a substantial right-twisted antiparallel β-sheet component based on CD analyses and descriptive deconvolution of the secondary structure. This NAcαS-FeII oligomer does not develop into the β-sheet fibrils that have become hallmarks of PD, even after extended incubation, as verified by TEM imaging and the fibril-specific OC antibody. Thioflavin T, a fluorescent probe for β-sheet fibril formation, also lacks coordination to this antiparallel conformer. This oligomeric state is not observed when O2 is excluded, indicating a role for iron(II) mediated O2 chemistry in locking this dynamic protein into a conformation that may have physiological or pathological implications. Conversely, copper-mediated NAcαS aggregation promotes fibrillar assembly. In fact, NAcαS-CuI activates O2 and subsequently promotes radical initiated oxidative modifications that are unique to the protein coordination site. Moreover, PD-relevant mutations alter the NAcαS folding dynamics, hindering protein-protein dityrosine coupling. Taken together, these results contribute to the ongoing conversation within the bioinorganic field about the role of metals and NAcαS in PD progression.

Metal redox chemistry promotes distinct structural assemblies of N-acetylated α-synuclein

256th National Meeting (2018)

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