2025-07-15 イェール大学
<関連情報>
- https://news.yale.edu/2025/07/15/neurons-use-built-backup-batteries-fuel-brain-under-stress
- https://www.pnas.org/doi/10.1073/pnas.2509003122
神経細胞における解糖系可塑性を支えるグリコーゲン Glycogen supports glycolytic plasticity in neurons
Milind Singh, Aaron D. Wolfe, Anjali A. Vishwanath, +4 , and Daniel Colón-Ramos
Proceedings of the National Academy of Sciences Published:July 10, 2025
DOI:https://doi.org/10.1073/pnas.2509003122
Significance
It has long been assumed that glycogen in the brain is primarily a glial energy reserve, with limited direct relevance to neurons. Yet, recent studies have demonstrated a role for glycogen in neuronal function. Here, we extend these findings, demonstrating that neurons directly metabolize glycogen to support glycolysis in vivo. Using a metabolic biosensor in Caenorhabditis elegans, we uncover a neuron-intrinsic, glycogen-dependent glycolytic plasticity that is specifically activated during hypoxia and mitochondrial dysfunction. This direct neuronal use of glycogen is essential for sustaining synaptic function, revealing an unexpected and critical role for glycogen in neuronal energy metabolism.
Abstract
Glycogen is the largest energy reserve in the brain, but the specific role of glycogen in supporting neuronal energy metabolism in vivo is not well understood. We established a system in Caenorhabditis elegans to dynamically probe glycolytic states in single cells of living animals via the use of the glycolytic sensor HYlight and determined that neurons can dynamically regulate glycolysis in response to activity or transient hypoxia. We performed an RNAi screen and identified that PYGL-1, an ortholog of the human glycogen phosphorylase, is required in neurons for glycolytic plasticity. We determined that neurons employ at least two mechanisms of glycolytic plasticity: glycogen-dependent glycolytic plasticity (GDGP) and glycogen-independent glycolytic plasticity. We uncover that GDGP is employed under conditions of mitochondrial dysfunction, such as transient hypoxia or in mutants for mitochondrial function. We find that the loss of GDGP impairs glycolytic plasticity and is associated with defects in synaptic vesicle recycling during hypoxia. Together, our study reveals that, in vivo, neurons can directly use glycogen as a fuel source to sustain glycolytic plasticity and synaptic function.
