Pathological accumulation of MAPT/tau protein is a defining feature of Alzheimer disease (AD) and related tauopathies, highlighting the need to identify druggable regulators of MAPT/tau clearance. Using Drosophila behavioral assays focused on cytoskeletal remodeling pathways dysregulated in AD, we identified genes whose genetic modulation mitigates MAPT/tau-induced behavioral deficits. These modifiers were validated by histopathology and mechanistically examined in human tauopathy cell models to determine their impact on autophagy-dependent MAPT/tau degradation. Autophagic flux, ATG9A trafficking, and autophagosome biogenesis were further analyzed. Across models, reduction of the phosphatase SSH1 consistently lowered steady-state MAPT/tau levels by enhancing autophagic flux through a mechanism distinct from its canonical regulation of CFL1. Mechanistically, SSH1 functions as a negative regulator of early autophagosome formation: SSH1 depletion promotes ATG9A mobilization to the endoplasmic reticulum-phagophore assembly site (ER-PAS), thereby accelerating autophagic vesicle biogenesis. Importantly, the MAPT/tau-lowering effect of Dmssh attenuation was abolished in flies haploinsufficient for DmAtg9, demonstrating that SSH1-mediated MAPT/tau clearance requires ATG9 function. Consistent with a direct regulatory interaction, in vitro phosphatase assays revealed that recombinant SSH1 decreases ATG9A phosphorylation in the presence of actin, identifying an SSH1-ATG9A regulatory axis controlling autophagosome initiation. These findings position SSH1 as a nodal inhibitor of autophagy initiation whose inhibition enhances MAPT/tau proteolysis. Notably, SSH1 haploinsufficiency also reduces SNCA/α-synuclein accumulation in vivo, indicating broader relevance to neurodegenerative proteopathies. By integrating in vivo functional screening with mechanistic studies in human cells, this work identifies SSH1 as a druggable phosphatase that constrains autophagy at the level of ATG9A-dependent vesicle formation.
