Copper Induced Radical Dimerization of α-Synuclein Requires Histidine.

Aggregation of the neuronal protein α-synuclein (αS) is a critical factor in the pathogenesis of Parkinson's disease. Analytical methods to detect post-translational modifications of αS are under development, yet the mechanistic underpinnings of biomarkers like dityrosine formation within αS have yet to be established. In our work, we demonstrate that Cu-bound N-terminally acetylated αS (αS) activates O resulting in both intermolecular dityrosine cross-linking within the fibrillar core as well as intramolecular cross-linking within the C-terminal region.

Iron Redox Chemistry Promotes Antiparallel Oligomerization of α-Synuclein.

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. In this Communication, we detail the influence of iron, a prevalent redox-active brain biometal, on the aggregation propensity and secondary structure of N-terminally acetylated αS (αS), the physiologically relevant form in humans. We demonstrate that under aerobic conditions, Fe(II) commits αS to a PD-relevant oligomeric assembly, 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.