Interaction and Redox Chemistry between Iron, Dopamine, and Alpha-Synuclein C-Terminal Peptides

a-Synuclein (aS), dopamine (DA), and iron have a crucial role in the etiology of Parkinson's disease. The present study aims to investigate the interplay between these factors by analyzing the DA/iron interaction and how it is affected by the presence of the C-terminal fragment of aS (Ac-aS(119-132)) that represents the iron-binding domain. At high DA:Fe molar ratios, the formation of the [Fe-III(DA)(2)](-) complex prevents the interaction with aS peptides, whereas, at lower DA:Fe molar ratios, the peptide is able to compete with one of the two coordinated DA molecules. This interaction is also confirmed by HPLC-MS analysis of the post-translational modifications of the peptide, where oxidized aS is observed through an inner-sphere mechanism. Moreover, the presence of phosphate groups in Ser129 (Ac-aS(p)S(119-132)) and both Ser129 and Tyr125 (Ac-aS(p)Y(p)S(119-132)) increases the affinity for iron(III) and decreases the DA oxidation rate, suggesting that this post-translational modification may assume a crucial role for the aS aggregation process. Finally, aS interaction with cellular membranes is another key aspect for aS physiology. Our data show that the presence of a membrane-like environment induced an enhanced peptide effect over both the DA oxidation and the [Fe-III(DA)(2)](-) complex formation and decomposition.