String/Cdc25 phosphatase is a suppressor of Tau-associated neurodegeneration

Abstract Tau pathology is defined by the intracellular accumulation of abnormally phosphorylated Tau and is prevalent in several neurodegenerative disorders. The identification of modulators of Tau abnormal phosphorylation and aggregation is key to understand disease progression and develop targeted therapeutic approaches. In this study we identify String/Cdc25 phosphatase as a suppressor of Tau abnormal phosphorylation and associated toxicity. Using a Drosophila model of tauopathy we show 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 provide 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 point-out Stg/Cdc25 based approaches as promising entry points to target abnormal Tau phosphorylation.