Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, 4200-135 Porto, Portugal.
PhD Program in Molecular and Cell Biology, Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, 4050-313 Porto, Portugal.
Dis Model Mech. 2023 Jan 1;16(1). doi: 10.1242/dmm.049693. Epub 2023 Jan 23.
Tau pathology is defined by the intracellular accumulation of abnormally phosphorylated Tau (MAPT) and is prevalent in several neurodegenerative disorders. The identification of modulators of Tau abnormal phosphorylation and aggregation is key to understanding disease progression and developing targeted therapeutic approaches. In this study, we identified String (Stg)/Cdc25 phosphatase as a suppressor of abnormal Tau phosphorylation and associated toxicity. Using a Drosophila model of tauopathy, we showed that Tau dephosphorylation by Stg/Cdc25 correlates with reduced Tau oligomerization, brain vacuolization and locomotor deficits in flies. Moreover, using a disease mimetic model, we provided evidence that Stg/Cdc25 reduces Tau phosphorylation levels independently of Tau aggregation status and delays neurodegeneration progression in the fly. These findings uncover a role for Stg/Cdc25 phosphatases as regulators of Tau biology that extends beyond their well-characterized function as cell-cycle regulators during cell proliferation, and indicate Stg/Cdc25-based approaches as promising entry points to target abnormal Tau phosphorylation.
tau 病理学的定义是细胞内异常磷酸化 tau（MAPT）的积累，并且在几种神经退行性疾病中普遍存在。鉴定 tau 异常磷酸化和聚集的调节剂是理解疾病进展和开发靶向治疗方法的关键。在这项研究中，我们确定了 String（Stg）/Cdc25 磷酸酶作为异常 tau 磷酸化和相关毒性的抑制剂。我们使用 tau 病的果蝇模型表明，Stg/Cdc25 对 tau 的去磷酸化与降低 tau 寡聚体形成、脑空泡化和果蝇运动缺陷相关。此外，使用疾病模拟模型，我们提供了证据表明，Stg/Cdc25 降低 tau 磷酸化水平独立于 tau 聚集状态，并在果蝇中延迟神经退行性变的进展。这些发现揭示了 Stg/Cdc25 磷酸酶作为 tau 生物学调节剂的作用，超出了它们在细胞增殖过程中作为细胞周期调节剂的特征功能，并表明基于 Stg/Cdc25 的方法是靶向异常 tau 磷酸化的有前途的切入点。
