Polyserine-mediated targeting of FAF2/UBXD8 ameliorates tau aggregation

Tau aggregation is a hallmark of several neurodegenerative disorders and gain of toxic functions of misfolded tau species are linked to pathobiology. Herein, we identified proteins that limit tau aggregation when targeted to tau aggregates by polyserine domains. Polyserine targeting was most effective at mitigating tau aggregation when fused to the VCP adaptor protein, FAF2/UBXD8. Surprisingly, FAF2/UBXD8 suppresses tau aggregation independent of VCP, but does require ubiquitination, membrane localization and a UBX domain. Validation in animal models demonstrated that polyserine-targeted FAF2/UBXD8 rescues tau-induced neurodegeneration in Drosophila. Further, delivery of targeted FAF2/UBXD8 reduced gliosis, seeding capacity and insoluble tau levels in PS19 tau transgenic mice while improving contextual fear conditioning. Collectively, our findings highlight polyserine as a tau targeting strategy and identify targeted FAF2/UBXD8 as a potent suppressor of tau pathology.