Increasing Brain Protein O-GlcNAc-ylation Mitigates Breathing Defects and Mortality of Tau.P301L Mice

The microtubule associated protein tau causes primary and secondary tauopathies by unknown molecular mechanisms. Post-translational O-GlcNAc-ylation of brain proteins was demonstrated here to be beneficial for Tau.P301L mice by pharmacological inhibition of O-GlcNAc-ase. Chronic treatment of ageing Tau.P301L mice mitigated their loss in body-weight and improved their motor deficits, while the survival was 3-fold higher at the pre-fixed study endpoint at age 9.5 months. Moreover, O-GlcNAc-ase inhibition significantly improved the breathing parameters of Tau.P301L mice, which underpinned pharmacologically the close correlation of mortality and upper-airway defects. O-GlcNAc-ylation of brain proteins increased rapidly and stably by systemic inhibition of O-GlcNAc-ase. Conversely, biochemical evidence for protein Tau.P301L to become O-GlcNAc-ylated was not obtained, nor was its phosphorylation consistently or markedly affected. We conclude that increasing O-GlcNAc-ylation of brain proteins improved the clinical condition and prolonged the survival of ageing Tau.P301L mice, but not by direct biochemical action on protein tau. The pharmacological effect is proposed to be located downstream in the pathological cascade initiated by protein Tau.P301L, opening novel venues for our understanding, and eventually treating the neurodegeneration mediated by protein tau.

微管相关蛋白tau（microtubule associated protein tau）可通过尚不明确的分子机制引发原发性与继发性tau蛋白病。本研究通过药物抑制O-糖基化酶（O-GlcNAc-ase），证实脑内蛋白质的翻译后O-GlcNAc修饰对Tau.P301L小鼠具有保护作用。对老年Tau.P301L小鼠进行长期给药，可减轻其体重丢失并改善运动功能缺陷；在预设的9.5月龄研究终点时，其存活率提升至原先的3倍。此外，O-糖基化酶抑制可显著改善Tau.P301L小鼠的呼吸参数，这从药理学上验证了死亡率与上气道缺陷之间的密切关联。全身性抑制O-糖基化酶可快速且稳定地提升脑内蛋白质的O-GlcNAc修饰水平。与之相反，本研究未检测到Tau.P301L蛋白发生O-GlcNAc修饰的生化证据，其磷酸化水平也未出现一致且显著的变化。我们得出结论：提升脑内蛋白质的O-GlcNAc修饰水平可改善老年Tau.P301L小鼠的临床状态并延长其存活时长，但该作用并非通过直接对tau蛋白产生生化修饰实现。研究推测，该药物效应位于Tau.P301L蛋白引发的病理级联反应的下游环节，这为我们理解tau蛋白介导的神经退行性病变并最终实现针对性治疗开辟了全新途径。