Glucose starvation induces tau phosphorylation leading to cellular stress response in fission yeast

Misfolded tau proteins and their accumulation cause many neurodegenerative diseases named tauopathies. While phosphorylation is required for tau protein activity, hyperphosphorylation leads to pathological conditions. Previous reports have shown that glucose deprivation might influence tau protein formation and phosphorylation in vivo, though its effect on cellular stress pathways in a yeast model has not been documented. In this study, we examined the various cellular processes, including oxidative and ER stress responses, glucose metabolism, autophagy, 20 S proteasomal activity, and glucose consumption in Schizosaccharomyces pombe cells heterologously expressing the human MAPT gene, which we obtained in our previous study. We observed increased levels of MAPT gene expression, phosphorylated tau protein (sites at Thr181, Thr231, and Ser396), and phosphorylated GSK-3β (site at Tyr216; contributes to tau phosphorylation) under glucose starvation conditions. The presence of tau protein led to increased expression levels of genes related to oxidative stress response and ER stress in fission yeast. Glucose-starved yeast expressing tau showed higher proteasomal activity and autophagy than control cells in normal glucose conditions. Additionally, cells containing tau protein exhibited higher glucose consumption under nutrient starvation conditions than those lacking tau. These findings indicate a possible relationship between increased tau protein phosphorylation and glucose metabolism, supporting the connection among tauopathies, poorly regulated blood sugar, and diabetes; thus, this provides initial evidence that S. pombe yeast can serve as a model for research in this area.