Citation: Schifano, F.; Dell’Acqua, S.; Nicolis, S.; Casella, L.; Monzani, E. Interaction and Redox Chemistry between Iron, Dopamine, and Alpha-Synuclein C-Terminal Peptides. Antioxidants 2023, 12, 791. https://doi.org/10.3390/ antiox12040791 Academic Editors: Vinood B. Patel and Mohammed Gulrez Zariwala Received: 25 February 2023 Revised: 17 March 2023 Accepted: 20 March 2023 Published: 24 March 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). antioxidants Article Interaction and Redox Chemistry between Iron, Dopamine, and Alpha-Synuclein C-Terminal Peptides Fabio Schifano 1,2 , Simone Dell’Acqua 1 , Stefania Nicolis 1 , Luigi Casella 1, * and Enrico Monzani 1, * 1 Department of Chemistry, University of Pavia, Via Taramelli 12, 27100 Pavia, Italy 2 IUSS School for Advanced Studies of Pavia, Palazzo del Broletto, Piazza della Vittoria 15, 27100 Pavia, Italy * Correspondence: luigi.casella@unipv.it (L.C.); enrico.monzani@unipv.it (E.M.) Abstract: 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-αS 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 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-αS p S 119–132 ) and both Ser129 and Tyr125 (Ac-αS 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 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 [Fe III (DA) 2 ] – complex formation and decomposition. Keywords: α-synuclein; iron; dopamine; Parkinson’s disease; oxidative stress 1. Introduction The interplay between iron, dopamine (DA), and α-synuclein (αS) seems to be a key feature of degenerating neurons in Parkinson’s disease (PD) [1]. In fact, from one side, it is well known that iron is able to exacerbate DA toxicity by promoting its oxidation to neurotoxic species [2], while, on the other hand, αS is able to bind to iron in both oxidation states [3]. The presence of an intracellular pool of labile, chelatable iron has long been recognized [4], and recent progress toward its characterization and distribution has been made in bacterial cells [5]. More iron can be released by damaged neurons, particularly those of the substantia nigra (SN), which contain the iron-rich neuromelanin pigment [6]. The dopaminergic neurons of SN are, in fact, particularly vulnerable to oxidative stress, mainly due to their direct involvement in DA metabolism which, if not controlled, can lead to the production of reactive quinones and ROS [7]. Furthermore, the produced quinones are able to react with proteins, like αS, thus preventing the protein from exerting its physiological role and ultimately leading to a vicious cycle in which the increased cytosolic DA exacerbates the oxidative stress [8]. Iron, being a redox-active transition metal, can promote DA oxidation (Scheme 1) by overcoming the spin restriction nature of dioxygen reduction. In addition, the produced superoxide and hydrogen peroxide can be converted into hydroxyl radical through Fenton- and Haber–Weiss-type reactions. Alongside the quinones and ROS production, iron–DA interaction can produce 6-hydroxydopamine, a neurotoxin used to simulate PD in animal models, although to a modest extent [2]. Antioxidants 2023, 12, 791. https://doi.org/10.3390/antiox12040791 https://www.mdpi.com/journal/antioxidants