Nitration and Glycation Diminish the α-Synuclein Role in the Formation and Scavenging of Cu2+-Catalyzed Reactive Oxygen Species

Human alpha-synuclein is a small monomeric protein (140 residues) essential to maintain the function of the dopaminergic neurons and the neuronal redox balance. However, it holds a dark side since it is able to clump inside the neurons forming insoluble aggregates known as Lewy bodies, which are considered the hallmark of Parkinson's disease. Sporadic mutations and nonenzymatic post-translational modifications are well-known to stimulate the formation of Lewy bodies. Yet, the effect of nonenzymatic post-translational modifications on the function of alpha-synuclein has been studied less intense. Therefore, here we study how nitration and glycation mediated by methylglyoxal affect the redox features of alpha-synuclein. Both diminish the ability of alpha-synuclein to chelate Cu2+, except when N-epsilon-(carboxyethyl)lysine or N-epsilon-(carboxymethyOlysine (two advanced glycation end products highly prevalent in vivo) are formed. This results in a lower capacity to prevent the Cu-catalyzed ascorbic acid degradation and to delay the formation of H2O2. However, only methylglyoxal was able to abolish the ability of alpha-synuclein to inhibit the free radical release. Both nitration and glycation enhanced the alpha-synuclein availability to be damaged by O-2(center dot-), although glycation made alpha-synuclein less reactive toward HO center dot. Our data represent the first report describing how nonenzymatic post-translational modifications might affect the redox function of alpha-synuclein, thus contributing to a better understanding of its pathological implications.