Dissociation of hyper-phosphorylated Tau from neuronal microtubules and its pathological aggregates, are hallmarks in the etiology of tauopathies. The Tau-microtubule interface is subject to polyglutamylation, a reversible posttranslational modification, increasing negative charge at tubulin C-terminal tails. Here, we asked whether tubulin polyglutamylation may contribute to Tau pathology in vivo. Since polyglutamylases modify various proteins other than tubulin, we generated a knock-in mouse carrying gene mutations to abolish Tuba4a polyglutamylation in a substrate-specific manner. We found that Tuba4a lacking C-terminal polyglutamylation prevents the binding of Tau and GSK3 kinase to neuronal microtubules, thereby strongly reducing phospho-Tau levels. Notably, crossbreeding of the Tuba4a knock-in mouse with the hTau tauopathy model, expressing a human Tau transgene, reversed hyper-phosphorylation and oligomerization of Tau and normalized microglia activation in brain. Our data highlight tubulin polyglutamylation as a potential therapeutic strategy in fighting tauopathies.

过度磷酸化的 Tau 从神经元微管及其病理聚集体中解离是 tau 病变病因学的标志。Tau-微管界面受到多谷氨酰化，一种可逆的翻译后修饰，增加微管蛋白 C 末端尾部的负电荷。在这里，我们询问微管蛋白多谷氨酰化是否可能导致体内 Tau 病理学。由于聚谷氨酰胺酶修饰微管蛋白以外的各种蛋白质，我们产生了携带基因突变的敲入小鼠，以底物特异性方式消除 Tuba4a 聚谷氨酰胺化。我们发现缺乏 C 末端多谷氨酰化的 Tuba4a 阻止了 Tau 和 GSK3 激酶与神经元微管的结合，从而大大降低了磷酸化 Tau 水平。值得注意的是，Tuba4a 敲入小鼠与 hTau tau 病模型的杂交，Tau转基因，逆转 Tau 的过度磷酸化和寡聚化，并使脑中的小胶质细胞活化正常化。我们的数据强调了微管蛋白多谷氨酰化作为对抗 tau 蛋白病的潜在治疗策略。