Redox Reactions of the α-Synuclein-Cu2+ Complex and Their Effects on Neuronal Cell Viability.

α-Synuclein (α-syn), a presynaptic protein believed to play an important role in neuropathology in Parkinson's disease (PD), is known to bind Cu2+. Cu2+ has been shown to accelerate the aggregation of α-syn to form various toxic aggregates in vitro. Copper is also a redox-active metal whose complexes with amyloidogenic proteins/peptides have been linked to oxidative stress in major neurodegenerative diseases. In this work, the formation of the Cu2+ complex with α-syn or with an N-terminal peptide, α-syn(1-19), was confirmed with electrospray-mass spectrometry (ES-MS). The redox potentials of the Cu2+ complex with α-syn (α-syn-Cu2+) and α-syn(1-19) were determined to be 0.018 and 0.053 V, respectively. Furthermore, the Cu2+ center(s) can be readily reduced to Cu+, and possible reactions of α-syn-Cu2+ with cellular species (e.g., O2, ascorbic acid, and dopamine) were investigated. The occurrence of a redox reaction can be rationalized by comparing the redox potential of the α-syn-Cu2+ complex to that of the specific cellular species. For example, ascorbic acid can directly reduce α-syn-Cu2+ to α-syn-Cu+, setting up a redox cycle in which O2 is reduced to H2O2 and cellular redox species is continuously exhausted. In addition, the H2O2 generated was demonstrated to reduce viability of the neuroblastoma SY-HY5Y cells. Although our results ruled out the direct oxidation of dopamine by α-syn-Cu2+, the H2O2 generated in the presence of α-syn-Cu2+ can oxidize dopamine. Our results suggest that oxidative stress is at least partially responsible for the loss of dopaminergic cells in PD brain and reveal the multifaceted role of the α-syn-Cu2+ complex in oxidative stress associated with PD symptoms. [ABSTRACT FROM AUTHOR]