title: Reactivity of copper-α-synuclein peptide complexes relevant to Parkinson's disease.
abstract: Parkinson's disease (PD) is a neurodegenerative disorder characterized by the presence of abnormal α-synuclein (αSyn) deposits in the brain. Alterations in metal homeostasis and metal-induced oxidative stress may play a crucial role in the aggregation of αSyn and, consequently, in the pathogenesis of PD. We have therefore investigated the capability of copper-αSyn6 and copper-αSyn15 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-αSyn 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 (kcat) of DTBCH2 catalytic oxidation are 0.030 s(-1) and 0.009 s(-1) for the reaction promoted by free copper(II) and [Cu(2+)-αSyn15], respectively. On the other hand, HPLC/ESI-MS analysis of solutions of αSyn15 incubated with copper(II) and 4-MC showed that αSyn 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 αSyn, also occurs on peptides not directly bound to copper, indicating that external αSyn can also be oxidized by copper. Therefore, this study strengthens the hypothesis that copper plays an important role in oxidative damage of αSyn which is proposed to be strongly related to the etiology of PD.
authors: Dipartimento di Chimica, Università di Pavia, Via Taramelli 12, 27100 Pavia, Italy. simone.dellacqua@unipv.it bioinorg@unipv.it.
authors: Simone
authors: S
authors: Dell'Acqua
authors: Valentina
authors: V
authors: Pirota
authors: Cecilia
authors: C
authors: Anzani
authors: Michela M
authors: MM
authors: Rocco
authors: Stefania
authors: S
authors: Nicolis
authors: Daniela
authors: D
authors: Valensin
authors: Enrico
authors: E
authors: Monzani
authors: Luigi
authors: L
authors: Casella
mesh_terms: D000595:Amino Acid Sequence; D002396:Catechols / Q000378:metabolism; D003300:Copper / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology; D051844:alpha-Synuclein / Q000737:chemistry / Q000378:metabolism*
chemical_list: D002396:Catechols; D051844:alpha-Synuclein; C018599:4-methylcatechol; C038096:tert-butylcatechol; D003300:Copper; C034221:catechol