Fig. 2

A schematic on how unregulated phosphorylation or oxidation of α-synuclein can disrupt iron and dopamine trafficking to lead to increased oxidative stress. Increased oxidation (a) or hyper-phosphorylation (b) of α-syn strongly reduces iron import through endocytosis of TfR (1). This leads to an initiation of alternative compensatory import mechanisms such as DMT1 expression to maintain cellular function (2). Elevation of iron by DMT1 restores DA production (3) but a lack of membrane bound α-syn causes impaired VMAT2-assisted transfer of DA into synaptic vesicles (4). The cytoplasmic location of oxidised (a) or phosphorylated (b) α-syn will also alter the location of DAT receptors on the cell surface and reduce recycling of extracellular DA (5). Elevation in cytoplasmic DA within a high labile iron environment generates toxic DA reactive quinones and promotes oxidative stress (6). Increased cytoplasmic DA may also lead to further post-translational modifications of α-syn, specifically the oxidation of methionines, thus increasing a propensity for α-syn to form aggregated species (7) and disrupt lipid membranes via lipid peroxidation (8). Once the oxidative damage produced from the interplay between modified α-syn, iron and DA outweighs protective antioxidant mechanisms, neuronal damage will be cyclically accelerated