human sod2 modification by dopamine quinones affects enzymatic activity by promoting its aggregation possible implications for parkinson’s disease人类sod2修改由多巴胺醌类影响酶活性,促进其聚合可能对帕金森病的影响.pdfVIP

Human SOD2 Modification by Dopamine Quinones Affects Enzymatic Activity by Promoting Its Aggregation: Possible Implications for Parkinson’s Disease 1. 1. 1 2 1 Elisa Belluzzi , Marco Bisaglia , Elisabetta Lazzarini , Leandro C. Tabares , Mariano Beltramini *, Luigi Bubacco1* ´ ´ 1 Department of Biology, University of Padova, Padova, Italy, 2 CEA, Institut de biologie et de technologies de Saclay, Service de Bioenergetique, Biologie Structurale et ´ Mecanismes, Gif-sur-Yvette, France Abstract Mitochondrial dysfunction and oxidative stress are considered central in dopaminergic neurodegeneration in Parkinson’s disease (PD). Oxidative stress occurs when the endogenous antioxidant systems are overcome by the generation of reactive oxygen species (ROS). A plausible source of oxidative stress, which could account for the selective degeneration of dopaminergic neurons, is the redox chemistry of dopamine (DA) and leads to the formation of ROS and reactive dopamine- quinones (DAQs). Superoxide dismutase 2 (SOD2) is a mitochondrial enzyme that converts superoxide radicals to molecular oxygen and hydrogen peroxide, providing a first line of defense against ROS. We investigated the possible interplay between DA and SOD2 in the pathogenesis of PD using enzymatic essays, site-specific mutagenesis, and optical and high- field-cw-EPR spectroscopies. Using radioactive DA, we demonstrated that SOD2 is a target of DAQs. Exposure to micromolar DAQ concentrations induces a loss of up to 50% of SOD2 enzymatic activity in a dose-dependent manner, whi