Tuning Glucose Dependence to Preserve Neuronal Function [Nov. 4, 2025]

Disrupted neuronal energy metabolism drives neurodegeneration by triggering cascades that lead to synaptic failure, neuronal loss, and clinical decline. Neurons primarily rely on OXPHOS. When OXPHOS is limited by hypoxia or mitochondrial dysfunction, they increase reliance on glycolysis. However, excessive glycolysis is harmful because toxic by-products accumulate. In Purkinje cells, ATG5-dependent autophagy limits GLUT2 and restrains glucose uptake, preventing glycolytic overdrive and supporting survival. In another study, neurons under stress mobilize endogenous glycogen to boost glycolysis as a metabolic backup and preserve function. Together, these findings show that neurons adjust their glycolytic reliance in response to environmental constraints.

Autophagy regulator ATG5 preserves cerebellar function by safeguarding its glycolytic activity (Nature Metabolism, 2025)
Summary: As one mechanism linking autophagy dysfunction to neurodegeneration, this study identifies an ATG5-dependent brake on GLUT2 that restrains glucose influx and glycolysis in Purkinje cells (PCs). When ATG5 is lost, GLUT2 accumulates, uptake rises, toxic glycolytic by-products build up, and PCs degenerate. Normalizing glucose uptake appears neuroprotective, and curbing excessive glycolysis may help.

Highlighted technique: To assess changes in glucose uptake in autophagy-deficient Purkinje cells, the authors used cerebellar organotypic slice cultures from mice and evaluated glucose uptake capacity by fluorescent microscopy using a fluorescent analog of glucose.

 Related techniques   Glucose Uptake Assay, Autophagy Detection

Glycogen supports glycolytic plasticity in neurons (PNAS, 2025)
Summary: This study visualizes neuronal metabolic shifts in vivo in C. elegans, showing that under mitochondrial dysfunction or hypoxia neurons engage glycogen-dependent glycolytic plasticity. It further demonstrates that neurons catabolize their own glycogen via the glycogen phosphorylase PYGL-1 to boost glycolysis. As a result, neurons can use glycogen as a metabolic backup to preserve function under stress.

Highlighted technique: In this study HYlight, a gene-encoded ratiometric fluorescent sensor for the glycolytic intermediate fructose-1,6-bisphosphate, was used to visualize cellular glycolytic activity in real time. The sensor combines an FBP-binding domain with a modified cpGFP, is excited at 405 and 488 nm, and upon FBP binding the two signals shift in opposite directions so changes in their ratio report increases or decreases in glycolysis.

 Related techniques   Glycolysis/OXPHOS Assay, Mitochondrial Membrane Potential

Previous Science Note