Alpha- and Gamma-Synucleins Regulate Energy Metabolism and Xanthine Oxidase Activity in Brain Cells

The process of signal transmission and transformation in the central nervous system requires active energy metabolism with high consumption of glucose and oxygen. Reactive oxygen species (ROS) produced as a result of these processes participate in intracellular signaling, but their overproduction leads to oxidative stress. Oxidative stress and α-synuclein aggregation are recognized as activators of neuronal death in Parkinson's disease. However, much less is known about the physiological role of monomeric synucleins. Using acute brain slices and primary co-cultures of cortical neurons and glial cells derived from transgenic animals with knockout of α-, β-, and γ-synuclein genes, we investigated the role of these proteins in ROS production and energy metabolism. We found that absence of synucleins leads to the reduced ROS production compared to the wild-type cells. The xanthine oxidase (XO) inhibitor led to the decrease in ROS production in the wild-type cells and the brain slices with β-synuclein knockout, whereas in the slices lacking α- or γ-synuclein, the XO inhibition was not observed, suggesting possible regulation of this enzyme by these proteins. Knockout of α- and γ-synucleins resulted in the decrease in mitochondrial membrane potential and reduction in energy capacity (in the form of ATP), which could be one of the mechanisms of XO regulation by synucleins.