美国贝勒医学院Huda Yahya Zoghbi研究团队发现，TYK2在tau病小鼠模型中调节tau水平、磷酸化和聚集。相关论文于2024年11月11日在线发表在《自然—神经科学》杂志上。

研究人员之前通过遗传筛选发现酪氨酸激酶2（TYK2）是tau水平的候选调节因子。研究人员验证了这一发现，发现TYK2能够在酪氨酸29（Tyr29）位点磷酸化tau，进而稳定tau并促进其在人体细胞中的聚集。研究人员发现，TYK2介导的Tyr29磷酸化干扰了tau的自噬清除。

此外，研究人员还展示了TYK2介导的Tyr29磷酸化促进了P301S tau转基因小鼠中的病理性tau积累。进一步地，Tyk2的敲低减少了总tau和致病tau水平，并在tau病小鼠模型中恢复了胶质反应。综合来看，这些数据表明，部分抑制TYK2可能是减少tau水平和毒性的策略。

研究人员表示，阿尔茨海默病是至少26种以tau阳性积累为特征的疾病之一，涉及神经元、胶质细胞或两者。然而，仍不清楚哪些修饰导致可溶性tau转变为不溶性聚集体。

附：英文原文

Title: TYK2 regulates tau levels, phosphorylation and aggregation in a tauopathy mouse model

Author: Kim, Jiyoen, Tadros, Bakhos, Liang, Yan Hong, Kim, Youngdoo, Lasagna-Reeves, Cristian, Sonn, Jun Young, Chung, Dah-eun Chloe, Hyman, Bradley, Holtzman, David M., Zoghbi, Huda Yahya

Issue&Volume: 2024-11-11

Abstract: Alzheimer’s disease is one of at least 26 diseases characterized by tau-positive accumulation in neurons, glia or both. However, it is still unclear what modifications cause soluble tau to transform into insoluble aggregates. We previously performed genetic screens that identified tyrosine kinase 2 (TYK2) as a candidate regulator of tau levels. Here we verified this finding and found that TYK2 phosphorylates tau at tyrosine 29 (Tyr29) leading to its stabilization and promoting its aggregation in human cells. We discovered that TYK2-mediated Tyr29 phosphorylation interferes with autophagic clearance of tau. We also show that TYK2-mediated phosphorylation of Tyr29 facilitates pathological tau accumulation in P301S tau-transgenic mice. Furthermore, knockdown of Tyk2 reduced total tau and pathogenic tau levels and rescued gliosis in a tauopathy mouse model. Collectively, these data suggest that partial inhibition of TYK2 could thus be a strategy to reduce tau levels and toxicity.

DOI: 10.1038/s41593-024-01777-2

Source: https://www.nature.com/articles/s41593-024-01777-2