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[摘要]：alpha-Synuclein (alpha-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 alpha-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 alpha-syn or with an N-terminal peptide, alpha-syn(1-19), was confirmed with electrospray-mass spectrometry (ES-MS). The redox potentials of the Cu2+ complex with alpha-syn (alpha-syn-Cu2+) and alpha-syn(1-19) were determined to be 0.018 and 0.053 V, respectively. Furthermore, the Cu2+ center(s) can be readily reduced to Cu2+ and possible reactions of alpha-syn-Cu2+) with cellular species (e.g., O-2, ascorbic acid, and dopamine) were investigated. The occurrence of a redox reaction can be rationalized by comparing the redox potential of the alpha-syn-Cu2+) complex to that of the specific cellular species. For example, ascorbic acid can directly reduce alpha-syn-Cu2+) to alpha-syn-Cu+, setting up a redox cycle in which O-2 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 alpha-syn-Cu2+, the H2O2 generated in the presence of alpha-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 alpha-syn-Cu2+ complex in oxidative stress associated with PD symptoms. |
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