The microtubule-associated protein tau oligomerizes, but the actions of oligomeric tau (oTau) are unknown. We have used Cry2-based optogenetics to induce tau oligomers (oTau-c). Optical induction of oTau-c elicits tau phosphorylation, aggregation, and a translational stress response that includes stress granules and reduced protein synthesis. Proteomic analysis identifies HNRNPA2B1 as a principle target of oTau-c. The association of HNRNPA2B1 with endogenous oTau was verified in neurons, animal models, and human Alzheimer brain tissues. Mechanistic studies demonstrate that HNRNPA2B1 functions as a linker, connecting oTau with N⁶-methyladenosine (m⁶A) modified RNA transcripts. Knockdown of HNRNPA2B1 prevents oTau or oTau-c from associating with m⁶A or from reducing protein synthesis and reduces oTau-induced neurodegeneration. Levels of m⁶A and the m⁶A-oTau-HNRNPA2B1 complex are increased up to 5-fold in the brains of Alzheimer subjects and P301S tau mice. These results reveal a complex containing oTau, HNRNPA2B1, and m⁶A that contributes to the integrated stress response of oTau.

微管相关蛋白 tau 寡聚化，但寡聚 tau (oTau) 的作用尚不清楚。我们使用基于 Cry2 的光遗传学来诱导 tau 寡聚体 (oTau-c)。oTau-c 的光诱导引发 tau 磷酸化、聚集和翻译应激反应，包括应激颗粒和蛋白质合成减少。蛋白质组学分析将 HNRNPA2B1 确定为 oTau-c 的主要靶标。HNRNPA2B1 与内源性 oTau 的关联已在神经元、动物模型和人类阿尔茨海默脑组织中得到验证。机制研究表明，HNRNPA2B1 作为连接子发挥作用，将 oTau 与 N ⁶ -甲基腺苷 (m ⁶ A) 修饰的 RNA 转录物连接起来。^{HNRNPA2B1 的敲低可防止 oTau 或 oTau-c 与 m 6} A结合或减少蛋白质合成，并减少 oTau 诱导的神经变性。在阿尔茨海默病受试者和 P301S tau 小鼠的大脑中，m ⁶ A 和 m ⁶ A-oTau-HNRNPA2B1 复合物的水平增加了 5 倍。这些结果揭示了含有 oTau、HNRNPA2B1 和 m ⁶ A 的复合物，有助于 oTau 的综合应激反应。