TAF15 amyloids propagate via defined motifs in a prion-like fashion.

TATA-box binding protein-associated factor 15 (TAF15) is an RNA-binding protein and the primary fibrillar constituent in a subset of frontotemporal lobar degeneration (FTLD) cases. However, the molecular determinants underlying TAF15 aggregation remain unclear. Here, we show that TAF15 forms amyloid fibrils under physiological conditions and develop a cellular biosensor to monitor its propagation. Both recombinant TAF15 fibrils and pathological aggregates extracted from FTLD patient brains selectively seed TAF15 biosensor cells, demonstrating prion-like properties. The closely related protein FUS does not seed TAF15 aggregation, revealing a cross-seeding barrier, but partially incorporates into inclusions during TAF15-induced seeding, potentially explaining their pathological overlap in FTLD. Computational and peptide-based mapping identifies aggregation-prone motifs within the low-complexity domain that stabilize ex vivo fibril cores and drive TAF15 propagation. These findings establish TAF15 as an amyloid-forming, prion-like protein and define sequence determinants underlying its self-assembly, providing a mechanistic framework for FTLD-TAF15 and potential therapeutic targets.