2. Academic Validation
  3. Polyserine-mediated targeting of FAF2/UBXD8 ameliorates tau aggregation

Polyserine-mediated targeting of FAF2/UBXD8 ameliorates tau aggregation

  • Neuron. 2025 Aug 29:S0896-6273(25)00587-2. doi: 10.1016/j.neuron.2025.08.002.
Meaghan Van Alstyne 1,  Georgia Brown 2,  Vanessa L Nguyen 3,  Mani Ramaswami 2,  Charles A Hoeffer 4,  Roy Parker 5
Affiliations

Affiliations

  • 1 Department of Biochemistry, University of Colorado, Boulder, CO, USA; Howard Hughes Medical Institute, University of Colorado, Boulder, CO, USA.
  • 2 Trinity College Institute of Neuroscience, School of Genetics and Microbiology, Smurfit Institute of Genetics and School of Natural Sciences, Trinity College Dublin, Dublin, Ireland.
  • 3 Department of Biochemistry, University of Colorado, Boulder, CO, USA.
  • 4 Department of Integrative Physiology, University of Colorado, Boulder, CO, USA.
  • 5 Department of Biochemistry, University of Colorado, Boulder, CO, USA; Howard Hughes Medical Institute, University of Colorado, Boulder, CO, USA; BioFrontiers Institute, University of Colorado, Boulder, CO, USA. Electronic address: roy.parker@colorado.edu.
PMID: 40902597 DOI: 10.1016/j.neuron.2025.08.002
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, 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.

Keywords

FAF2; UBXD8; neurodegeneration; polyserine; protein aggregation; tau; tauopathy.

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