Polyserine-mediated targeting of FAF2/UBXD8 ameliorates tau aggregation.

ABSTRACT: Tau aggregation is a hallmark of several neurodegenerative disorders, and the gain of toxic function of misfolded tau species is 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 vasolin-containing protein (VCP) adaptor protein fas-associated factor family member 2/UBX domain-containing protein 8 (FAF2/UBXD8). Surprisingly, FAF2/UBXD8 suppresses tau aggregation independent of VCP but does require ubiquitination, membrane localization, and a ubiquitin regulator X (UBX) domain. Validation in animal models demonstrated that polyserine-targeted FAF2/UBXD8 rescues tau-induced neurodegeneration in Drosophila. Further, deliv

SUBMITTER: Van Alstyne M 

PROVIDER: S-EPMC12422715 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature