Nuclear tau aggregates inhibit RNA export and form by secondary seeding from cytosolic tau aggregates

Tau aggregates contribute to multiple neurodegenerative diseases including frontotemporal dementia and Alzheimer's disease (AD). In models of tauopathy and in patient tissue, tau aggregates can form in the cytoplasm, perinuclear region, and nucleus. Using a HEK293T tau biosensor system, we identified that cytoplasmic tau aggregates formed first, followed by perinuclear-ring-like tau assemblies, and then nuclear tau aggregates formed in nuclear speckles. Nuclear tau aggregates only form in cells with pre-existing cytoplasmic tau aggregates and mostly form independently of cells traversing mitosis. Finally, nuclear tau aggregates do not contain exogenous tau seeds and arise by a secondary seeding event dependent on VCP. Nuclear tau aggregates inhibit mRNA export and show a twofold increase in poly-adenylated mRNAs in the nucleus. Together, these findings indicate that nuclear tau aggregation alters RNA biogenesis and occurs by a secondary seeding event from cytoplasmic tau aggregates, which could contribute to tau pathology.