Autophagy regulator ATG5 preserves cerebellar function by safeguarding its glycolytic activity

Abstract Dysfunctions in autophagy, a cellular mechanism for breaking down components within lysosomes, often lead to neurodegeneration. The specific mechanisms underlying neuronal vulnerability to autophagy dysfunction remain elusive. Here, we show that autophagy contributes to the survival of cerebellar Purkinje cells (PCs) by safeguarding their glycolytic activity. This function of autophagy is independent of its conventional housekeeping role and involves ATG5-mediated regulation of glucose transporter 2 (GLUT2) levels during cerebellar maturation. Autophagy-deficient PCs exhibit GLUT2 accumulation on the plasma membrane, along with increased glucose uptake and accelerated glycolysis. We identify lysophosphatidic acid and serine as glycolytic intermediates that trigger PC death and demonstrate that deletion of GLUT2 in ATG5-deficient mice mitigates PC neurodegeneration and restores their ataxic gait. Taken together, this work reveals a novel mechanism for regulating GLUT2 levels in neurons and provides new insights into the neuroprotective role of autophagy by controlling glucose homeostasis in the brain.