Neuronal Glycogen Breakdown Mitigates Tauopathy via Pentose Phosphate Pathway-Mediated Oxidative Stress Reduction

Our findings show that dietary protein restriction partially rescues the tau phenotype in a Drosophila melanogaster model of tauopathy. Our Cox proportional hazard ratio analysis (Coxph_proportional hazard ratio file contains the code) revealed a significant interaction between diet and tauopathies.
In a Drosophila melanogaster tauopathy model and AD patient brain, we identified distinct signatures of impaired glycogen metabolism, suggesting a link between tauopathies and glycogen dysregulation. We demonstrate that enhancing neuronal glycogen breakdown via glycogen phosphorylase (GlyP) activation mitigates tauopathy phenotypes in flies and induced pluripotent stem cell (iPSC)-derived neurons from FTLD-tau patients.
Notably, our RNA-seq analysis and targeted metabolomic analysis comparing GlyPWT-overexpressing tau flies and control GlyPS15A (non-functional GlyP) flies showed that glycogen breakdown redirects glucose flux toward the pentose phosphate pathway, reducing oxidative stress and promoting neuroprotection.
Together, our studies identify impaired glycogen metabolism as a key hallmark of tauopathies and propose glycogen regulation as a promising therapeutic target for tauopathies and other neurodegenerative diseases.