Differences in the binding of copper(I) to α- and ß-synuclein.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the presence of abnormal α-synuclein (αS) deposits in the brain. Alterations in homeostasis and metal-induced oxidative stress may play a crucial role in the progression of αS amyloid assembly and pathogenesis of PD. Contrary to αS, ß-synuclein (ßS) is not involved in the PD etiology. However, it has been suggested that the ßS/αS ratio is altered in PD, indicating that a correct balance of these two proteins is implicated in the inhibition of αS aggregation. αS and ßS share similar abilities to coordinate Cu(II). In this study, we investigated and compared the interaction of Cu(I) with the N-terminal portion of ßS and αS by means of NMR, circular dichroism, and X-ray absorption spectroscopies. Our data show the importance of M10K mutation, which induces different Cu(I) chemical environments. Coordination modes 3S1O and 2S2O were identified for ßS and αS, respectively. These new insights into the bioinorganic chemistry of copper and synuclein proteins are a basis to understand the molecular mechanism by which ßS might inhibit αS aggregation.