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

Antioxidants (Basel). 2023 Mar 24;12(4):791. doi: 10.3390/antiox12040791.


α-Synuclein (αS), 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 αS (Ac-αS119-132) that represents the iron-binding domain. At high DA:Fe molar ratios, the formation of the [FeIII(DA)2]- complex prevents the interaction with αS 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 αS is observed through an inner-sphere mechanism. Moreover, the presence of phosphate groups in Ser129 (Ac-αSpS119-132) and both Ser129 and Tyr125 (Ac-αSpYpS119-132) 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 αS aggregation process. Finally, αS interaction with cellular membranes is another key aspect for αS physiology. Our data show that the presence of a membrane-like environment induced an enhanced peptide effect over both the DA oxidation and the [FeIII(DA)2]- complex formation and decomposition.

Keywords: Parkinson’s disease; dopamine; iron; oxidative stress; α-synuclein.