Yılmazer Merve, Şengelen Aslıhan, Aksüt Yunus, Palabıyık Bedia, Önay-Uçar Evren, Karaer Uzuner Semian
Department of Molecular Biology and Genetics, Faculty of Science, Istanbul University, Vezneciler, Istanbul, 34134, Turkey.
Department of Molecular Biology and Genetics, Basic Medical Sciences, School of Medicine, Koç University, Istanbul, Turkey.
Arch Microbiol. 2025 May 19;207(7):148. doi: 10.1007/s00203-025-04350-y.
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.
错误折叠的tau蛋白及其聚集会引发许多被称为tau蛋白病的神经退行性疾病。虽然tau蛋白的活性需要磷酸化，但过度磷酸化会导致病理状况。先前的报道表明，葡萄糖剥夺可能会在体内影响tau蛋白的形成和磷酸化，不过其对酵母模型中细胞应激途径的影响尚未见文献记载。在本研究中，我们检测了多种细胞过程，包括氧化应激和内质网应激反应、葡萄糖代谢、自噬、20S蛋白酶体活性以及在异源表达人类MAPT基因的粟酒裂殖酵母细胞中的葡萄糖消耗情况，该基因是我们在先前研究中获得的。我们观察到在葡萄糖饥饿条件下，MAPT基因表达水平、磷酸化tau蛋白（苏氨酸181、苏氨酸231和丝氨酸396位点）以及磷酸化GSK - 3β（酪氨酸216位点；有助于tau蛋白磷酸化）的水平均有所升高。tau蛋白的存在导致裂殖酵母中与氧化应激反应和内质网应激相关的基因表达水平增加。与正常葡萄糖条件下的对照细胞相比，表达tau蛋白的葡萄糖饥饿酵母表现出更高的蛋白酶体活性和自噬水平。此外，在营养饥饿条件下，含有tau蛋白的细胞比缺乏tau蛋白的细胞表现出更高的葡萄糖消耗。这些发现表明tau蛋白磷酸化增加与葡萄糖代谢之间可能存在关联，支持了tau蛋白病、血糖调节不良和糖尿病之间的联系；因此，这提供了初步证据，证明粟酒裂殖酵母可作为该领域研究的模型。
