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, which is correlated to the concomitant formation of protein aggregates, while the coordination geometry of the active site appears unaffected by DAQ modifications. Our findings support a model in which DAQ-mediated SOD2 inactivation increases mitochondrial ROS production, suggesting a link between oxidative stress and mitochondrial dysfunction.
Highlights
Parkinson disease (PD) is a multifactorial neurodegenerative condition characterized by the progressive loss of dopaminergic neurons in the Substantia Nigra pars compacta and by the presence of intracellular inclusions, known as Lewy bodies, in surviving neurons
We recently characterized the structural modifications and functional effects induced by DAQs on DJ-1, a protein involved in PD proposed to act as an oxidative stress sensor [7], and on a-synuclein, a protein involved in familiar forms of PD and the major component of Lewy bodies [8,9,10]
Interaction between Superoxide dismutase 2 (SOD2) and DAQs To assess whether DAQs could react with SOD2, the reactions were first followed by UV-vis spectroscopy
Summary
Parkinson disease (PD) is a multifactorial neurodegenerative condition characterized by the progressive loss of dopaminergic neurons in the Substantia Nigra pars compacta and by the presence of intracellular inclusions, known as Lewy bodies, in surviving neurons. Oxidative stress occurs when the capacity of the endogenous antioxidant systems are overcome by the generation of reactive oxygen species (ROS), which leads to cellular damage and death. A possible mechanism involved in the increase of oxidative stress, which could account for the preferential degeneration of dopaminergic neurons in PD, involves the redox reactions specific of dopamine (DA). Several different pathways have been identified for the oxidation of DA [2] These reactions lead to both toxic ROS and dopamine-quinones (DAQs) [3]. We recently characterized the structural modifications and functional effects induced by DAQs on DJ-1, a protein involved in PD proposed to act as an oxidative stress sensor [7], and on a-synuclein, a protein involved in familiar forms of PD and the major component of Lewy bodies [8,9,10]
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