Inactivation of Laforin Phosphatase and Increased Glucose Uptake Underlie Glycogen Synthase-Mediated Neuronal Survival Under Oxidative Stress.

Recent studies demonstrate that exposure of neurons to physiological stressors triggers glycogen synthase (GS) activation and glycogen synthesis as a transient cell survival mechanism. However, the mechanisms that regulate glycogen synthesis during stress and its role in neuronal physiology remain unclear. This study investigated the mechanisms that guide GS activation and glycogen accumulation under oxidative stress conditions as a model stressor. We use neuronal cell lines to demonstrate that hydrogen peroxide-induced oxidative stress activates GS and glycogen synthesis in neuronal cells. We further demonstrate that the stress-induced glycogen accumulation is dependent on the membrane localization of the Glut3 glucose transporters and increased glucose uptake during stress. The stress-induced activation of glycogen synthesis, however, is independent of intracellular glucose level, suggesting a parallel mechanism for activating GS and glucose uptake in neurons under physiological stress. We demonstrate that oxidative stress results in the inactivation of laforin phosphatase, leading to the membrane localization of Glut3 and activation of GS. Using the Drosophila model, we demonstrate that increased GS activity and concomitant glycogen accumulation are pro-survival mechanisms for neurons under oxidative stress. Our study thus offers novel insights into the pathways that regulate glycogen metabolism in neurons under oxidative stress and underscores their importance for neuronal survival.