Reactivity of copper-α-synuclein peptide complexes relevant to Parkinson's disease

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the presence of abnormal alpha-synuclein (alpha Syn) deposits in the brain. Alterations in metal homeostasis and metal-induced oxidative stress may play a crucial role in the aggregation of alpha Syn and, consequently, in the pathogenesis of PD. We have therefore investigated the capability of copper-alpha Syn6 and copper-alpha Syn15 peptide complexes, with the 1-6 and 1-15 terminal fragments of the protein, to promote redox reactions that can be harmful to other cellular components. The pseudo-tyrosinase activity of copper-alpha Syn complexes against catecholic (di-tert-butylcatechol (DTBCH2), 4-methylcatechol (4-MC)) and phenolic (phenol) substrates is lower compared to that of free copper(II). In particular, the rates (k(cat)) of DTBCH2 catalytic oxidation are 0.030 s(-1) and 0.009 s(-1) for the reaction promoted by free copper(II) and [Cu2+-alpha Syn15], respectively. On the other hand, HPLC/ESI-MS analysis of solutions of alpha Syn15 incubated with copper(II) and 4-MC showed that alpha Syn is competitively oxidized with remarkable formation of sulfoxide at Met1 and Met5 residues. Moreover, the sulfoxidation of methionine residues, which is related to the aggregation of alpha Syn, also occurs on peptides not directly bound to copper, indicating that external alpha Syn can also be oxidized by copper. Therefore, this study strengthens the hypothesis that copper plays an important role in oxidative damage of alpha Syn which is proposed to be strongly related to the etiology of PD.