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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月14日

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  • Katerina Konstantoulea,
  • Laxmikant Gadhe,
  • Frank Goodavish,
  • Ankit Gupta,
  • Harichandra D. Tagad,
  • Jaime Vaquer-Alicea,
  • Nikhil B. Ghayal,
  • Shanu F. Roemer,
  • Michael A. DeTure,
  • Alissa L. Nana,
  • Salvatore Spina,
  • Lea T. Grinberg,
  • William W. Seeley,
  • Dennis W. Dickson,
  • Charles L. White III,
  • Marc I. Diamond,
  • Nikolaos N. Louros

摘要

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.