Tau drives translational selectivity by interacting with ribosomal proteins. Tau drives translational selectivity by interacting with ribosomal proteins

There is a fundamental gap in understanding the consequences of tau-ribosome interactions. Tau oligomers and filaments hinder protein synthesis in vitro, and they associate strongly with ribosomes in vivo. Here, we investigated the consequences of tau interactions with ribosomes in vivo and in human brain tissues to identify tau as a direct modulator of ribosomal selectivity. We performed microarrays and nascent proteomics to measure changes in protein synthesis using rTg4510 tau transgenic mice. We determined that tau expression differentially shifts the transcriptome and the proteome and that the synthesis of ribosomal proteins is reversibly dependent on tau levels. We further extended these results to human brains and show that tau pathologically interacts with ribosomal protein S6 (rpS6 or S6). Consequently, synthesis of ribosomal proteins coded by 5’TOP-mRNAs was reduced under tauopathic conditions in Alzheimer’s disease brains. Our data establish tau as a driver of RNA translation selectivity. Moreover, considering that regulation of protein synthesis is critical to learning and memory, aberrant tau-ribosome interactions in disease could explain the linkage between virtually every tauopathy and cognitive impairment and memory decline. Overall design: Nontransgenic mice and rTg4510 tau transgenic mice were fed either normal feed or doxycycline to suppress transgenic tau expression. Biological replicates: Non + veh = 3, Non + dox = 2, Tg + veh = 3, Tg + dox = 3

目前学界对tau蛋白（tau）与核糖体相互作用所产生的影响仍存在根本性认知空白。体外实验显示，tau寡聚体与纤维丝会阻碍蛋白质合成，且它们在体内可与核糖体紧密结合。本研究通过在体内及人类脑组织中探究tau与核糖体相互作用的影响，证实tau可直接调控核糖体的翻译选择性。我们以rTg4510 tau转基因小鼠为模型，利用微阵列（microarray）技术与新生蛋白质组学方法检测蛋白质合成的变化。研究发现，tau的表达会使转录组与蛋白质组发生差异性改变，且核糖体蛋白的合成可逆地依赖于tau的表达水平。我们进一步将该结论拓展至人类脑组织研究，证实tau可与核糖体蛋白S6（rpS6或称S6）发生病理性相互作用。因此，在阿尔茨海默病患者脑组织的tau病变状态下，由5'末端寡聚嘧啶mRNA（5'TOP-mRNA）编码的核糖体蛋白合成水平出现下降。本研究数据证实tau是调控RNA翻译选择性的核心驱动因素。此外，鉴于蛋白质合成的调控对于学习与记忆至关重要，疾病状态下异常的tau-核糖体相互作用，或可解释几乎所有tau蛋白病与认知损伤、记忆衰退之间的关联。实验整体设计：将非转基因小鼠与rTg4510 tau转基因小鼠分别饲喂正常饲料或多西环素（doxycycline）以抑制转基因tau的表达。生物学重复设置：非转基因+溶剂组（Non + veh）=3，非转基因+多西环素组（Non + dox）=2，转基因+溶剂组（Tg + veh）=3，转基因+多西环素组（Tg + dox）=3