Evidence for Copper-dioxygen Reactivity during α-Synuclein Fibril Formation

摘要

Amyloid formation of the presynaptic protein a-synuclein (α-syn), a process that has been implicated in the pathogenic mechanism of Parkinson's disease, has been shown to accelerate in the presence of copper. In fact, Cu/protein interactions also are associated with other neurodegenerative ailments such as Alzheimer's and prion diseases. Cu is a redox-active metal ion that can activate O_2 leading to the generation of reactive oxygen species (ROS) such as O_2~(-·) HO_2(-·), HO~(-·), and H_2O_2, which can in turn lead to enhanced oxidative stress and/or protein damage. In addition, metal coordination can perturb protein structure or initiate protein misfolding events, both of which could lead to altered function. In this work, the Cu~(II) coordination site of α-syn (Figure 1) is explored in the soluble and fibrillar states and evidence of Cu~I/O_2 chemistry is reported.