Intraneuronal accumulation of hyperphosphorylated tau is a pathological hallmark of several neurodegenerative disorders, including Alzheimer's disease. Phosphorylation plays a crucial role in modulating the tau‐microtubule interaction and the ability of the protein to aggregate, but despite efforts during the past decades, the real identity of the kynases involved in vivo remains uncertain. Here, for the first time, we demonstrate that the cGMP‐dependent protein kinase G (PKG) phosphorylates tau in both in vitro and in vivo models. More intriguingly, we provide evidence that PKG phosphorylates tau at Ser214 but not at Ser202, a condition that could reduce the pathological aggregation of the protein shifting tau from a pro‐aggregant to a neuroprotective anti‐aggregant conformation.

中文翻译：

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蛋白激酶 G 在不同的 Ser/Thr 位点磷酸化与阿尔茨海默病相关的 tau 蛋白


神经元内过度磷酸化 tau 蛋白的积累是包括阿尔茨海默氏病在内的多种神经退行性疾病的病理标志。磷酸化在调节 tau 微管相互作用和蛋白质聚集能力方面发挥着至关重要的作用，但尽管过去几十年做出了努力，体内涉及的激酶的真实身份仍然不确定。在这里，我们首次证明 cGMP 依赖性蛋白激酶 G (PKG) 在体外和体内模型中磷酸化 tau。更有趣的是，我们提供的证据表明 PKG 在 Ser214 位点磷酸化 tau，但不在 Ser202 位点磷酸化，这种情况可以减少蛋白质的病理性聚集，使 tau 从促聚集构象转变为神经保护性抗聚集构象。