Human SOD2 Modification by Dopamine Quinones Affects Enzymatic Activity by Promoting Its Aggregation: Possible Implications for Parkinson’s Disease

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.

In vivo protein targets for increased quinoprotein adduct formation in aged substantia nigra

“…Previous in vitro studies have identified various protein targets, including α-synuclein (Bisaglia et al, 2007(Bisaglia et al, , 2010Marques andOuteiro, 2012), parkin (LaVoie et al, 2005), DJ-1 (Girotto et al, 2012), tyrosine hydroxylase , superoxide dismutase 2 (SOD2) (Belluzzi et al, 2012), glutathione peroxidase 4 (GPx4) (Hauser et al, 2013), and a variety of mitochondrial proteins (Van Laar et al, 2009). However, the in vivo protein targets for quinone modification, particularly proteins with increased quinone modification in aged SN, were completely unknown.…”

“…While previous in vitro studies were mostly based on educated guess or labeling isolated mitochondria or cultured cells with 14 C-dopamine (Belluzzi et al, 2012;Bisaglia et al, 2007Bisaglia et al, , 2010Girotto et al, 2012;Hauser et al, 2013;; LaVoie et al, 2005; Marques and Outeiro, 2012; Van Laar et al, Fig. 8.…”

Splice Variant Biomarkers for Parkinson's Disease

“…Given its antioxidant capacity, it has been implicated in the pathogenesis of PD. For example, inactivation of SOD2 increases mitochondrial ROS production in in vitro models of PD (Belluzzi, et al, 2012). Moreover, SOD2 protein levels are increased in the frontal cortex of PD patients (Ferrer, et al, 2007).…”

Systematic literature review on Parkinson's disease and Childhood Leukaemia and mode of actions for pesticides

“…The redox chemistry of dopamine could elicit cytotoxic effects such that it could result in ROS production and formation of dopamine-quinones (DAQs). For example, DAQs inactivated superoxide dismutase 2 (SOD2), a mitochondrial enzyme that converts superoxide to molecular oxygen and hydrogen peroxide as a defence response against ROS, leading to increased ROS level and oxidative stress (Belluzzi et al, 2012). Another study reported that DAQ can induce various forms of mitochondrial dysfunction such as mitochondrial swelling and decreased electron transport chain activity (Bisaglia et al, 2010).…”