Increase in brain glycogen levels ameliorates disease phenotype and rescues neurodegeneration in the Drosophila model of Huntington's disease.

Under normal physiological conditions, the mammalian brain contains very little glycogen, most of which is stored in astrocytes. However, the aging brain and subareas of the brain in patients with neurodegenerative disorders tend to accumulate glycogen, the cause and significance of which remain largely unexplored. Using cellular models, we have recently demonstrated a neuroprotective role for neuronal glycogen and glycogen synthase in the context of Huntington's disease. To gain insight into the role of brain glycogen in regulating proteotoxicity, we utilized a Drosophila model of Huntington's disease in which glycogen synthase was either knocked down or expressed ectopically. Enhancing glycogen synthesis in the brains of flies with Huntington's disease decreased mutant Huntingtin aggregation and reduced oxidative stress by activating auto-lysosomal functions. Further, the overexpression of glycogen synthase in the brain rescues photoreceptor degeneration, improves locomotor deficits, and increases fitness traits in Huntington's disease model. We thus provide in vivo evidence for the neuroprotective functions of glycogen synthase and glycogen in neurodegenerative conditions and their role in the neuronal autophagy process.