Aggregation and propagation of TAF15 trigger neurodegeneration.

Protein misfolding and propagation contribute to neurodegenerative diseases. Recently, cryogenic electron microscopy of insoluble amyloid fibrils derived from individuals with frontotemporal lobar degeneration (FTLD) revealed new species of amyloid fibrils, which are composed of aggregated TATA-binding protein-associated factor 15 (TAF15). However, it remains unknown whether TAF15 fibrils propagate in a prion-like manner and drive neurodegeneration. Here, we show that TAF15 forms amyloid fibrils that can self-propagate. Strikingly, a single injection of synthetic TAF15 pre-formed fibrils into the prefrontal cortex of wild-type mice led to the aggregation of endogenous TAF15 and cell-to-cell transmission of pathologic TAF15. TAF15 pathology was accompanied by progressive degeneration of cortical neurons, cognitive impairments, and anxiety- and depression-like behaviors. The detrimental effects of TAF15 fibrils were abolished by genetic deletion of endogenous TAF15. Together, these observations indicate that TAF15 aggregation drives neurodegeneration.