Aggregation of α-synuclein induced by the Cu,Zn-superoxide dismutase and hydrogen peroxide system

Alpha-synuclein is a major component of the abnormal protein aggregation in Lewy bodies of Parkinson’s disease (PD) and senile plaques of Alzheimer’s disease (AD). Previous studies have shown that the aggregation of α-synuclein was induced by copper (II) and H2O2 system. Since copper ions could be released from oxidatively damaged Cu,Zn-superoxide dismutase (SOD), we investigated the role of Cu,Zn-SOD in the aggregation of α-synuclein. When α-synuclein was incubated with both Cu,Zn-SOD and H2O2, α-synuclein was induced to be aggregated. This process was inhibited by radical scavengers and spin trapping agents such as 5,5′-dimethyl 1-pyrolline N-oxide and tert-butyl-α-phenylnitrone. Copper chelators, diethyldithiocarbamate and penicillamine, also inhibited the Cu,Zn-SOD/H2O2 system-induced α-synuclein aggregation. These results suggest that the aggregation of α-synuclein is mediated by the Cu,Zn-SOD/H2O2 system via the generation of hydroxyl radical by the free radical-generating function of the enzyme. The Cu,Zn-SOD/H2O2-induced α-synuclein aggregates displayed strong thioflavin-S reactivity, reminiscent of amyloid. These results suggest that the Cu,Zn-SOD/H2O2 system might be related to abnormal aggregation of α-synuclein, which may be involved in the pathogenesis of PD and related disorders.