Role of Cytochrome c as a Stimulator of α-Synuclein Aggregation in Lewy Body Disease

α-Synuclein is a major component of aggregates forming amyloid-like fibrils in diseases with Lewy bodies and other neurodegenerative disorders, yet the mechanism by which α-synuclein is intracellularly aggregated during neurodegeneration is poorly understood. Recent studies suggest that oxidative stress reactions might contribute to abnormal aggregation of this molecule. In this context, the main objective of the present study was to determine the potential role of the heme protein cytochrome c in α-synuclein aggregation. When recombinant α-synuclein was coincubated with cytochrome c/hydrogen peroxide, α-synuclein was concomitantly induced to be aggregated. This process was blocked by antioxidant agents such asN-acetyl-l-cysteine. Hemin/hydrogen peroxide similarly induced aggregation of α-synuclein, and both cytochromec/hydrogen peroxide- and hemin/hydrogen peroxide-induced aggregation of α-synuclein was partially inhibited by treatment with iron chelator deferoxisamine. This indicates that iron-catalyzed oxidative reaction mediated by cytochrome c/hydrogen peroxide might be critically involved in promoting α-synuclein aggregation. Furthermore, double labeling studies for cytochromec/α-synuclein showed that they were colocalized in Lewy bodies of patients with Parkinson's disease. Taken together, these results suggest that cytochrome c, a well known electron transfer, and mediator of apoptotic cell death may be involved in the oxidative stress-induced aggregation of α-synuclein in Parkinson's disease and related disorders.