The Effect of Copper on the Self-Assembly of α-Synuclein Oligomers in Parkinson`s Disease

α-Synuclein (AS) oligomers are major hallmarks of Parkinson`s disease (PD). The sequence of AS is divided to three domains (Figure 1): amphipathic domain (residues 1-60), the non-amyloid-β component (NAC, residues 61-95) which promote aggregation and the acidic region (residues 96-140). Clinical studies showed that cerebrospinal fluid of PD patients have elevated levels of copper which can promote AS aggregation.¹ In vitro studies have shown that copper may bind to AS monomer in three binding sites (Figure 1): Met1-Asp2 in the amphipathic domain; His50 in the amphipathic domain and Asp119 and Asp121-Glu123 in the acidic region. However, these binding sites in AS oligomers have not yet been studied at the molecular level.

Two structural models of the self-assembled full-length AS oligomer have been solved; one by ssNMR and the second in our group.^2,3 We examined the effect of various concentrations of copper on the three binding sites in each of the models. Our work shows that at high concentrations of copper, the copper ions bind both to the amphipathic and the acidic regions to the ssNMR model. At low concentrations, copper ions prefer to bind to the amphipathic region in the ssNMR model. In the computational model, copper prefers to bind to the amphipathic domain both at high and low copper concentrations. Our study illustrates polymorphic states of AS oligomers and that copper increase the polymorphism, due to the various binding sites along the domains. Future therapeutic strategies should consider the polymorphism of AS with absence and with presence of copper.

Figure 1: A scheme of the sequence of AS and the three possible binding sites in AS monomer.

1. Wineman-Fisher, V.et al. Coord. Chem. Rev. 327–328, 20–26 (2016).
2. Tuttle, M. D. et al. Nat. Struct. Mol. Biol. 23, 1–9 (2016).
3. Bloch, D.N. et al. ACS Omega 2, 3363–3370 (2017).