Acknowledgements: We thank the individuals and their families for donating brain tissue; the Queen Square Brain Bank for Neurological Disorders at University College London Queen Square Institute of Neurology, which receives support from the Reta Lila Weston Institute for Neurological Studies, for supplying tissue from individuals 2 and 3; J. Grafman for supplying tissue from individual 4; M. Jacobsen for help with neuropathological examinations; R. Richardson, K. Cox and N. Maynard for help with histology and immunohistochemistry; J. Grimmett, T. Darling and I. Clayson for help with high-performance computing; K. Yamashita and G. Murshudov for help with model refinements; and T. Behr, A. Bertolotti, R. Chen, S. Davies, M. Goedert, D. Hilvert and S. Scheres for discussions. This work was supported by the electron microscopy and scientific computing facilities at the MRC Laboratory of Molecular Biology and by the Center for Medical Genomics at the Indiana University School of Medicine. This work was supported by the Medical Research Council as part of United Kingdom Research and Innovation (also known as UK Research and Innovation) (no. MC_UP_1201/25 to B.R.-F.); the US National Institutes of Health (nos. U01-NS110437, RF1-AG071177 and R01-AG080001 to R.V. and B.G.); the Alzheimer’s Society (nos. AS-PG-18-004 and AS-PG-21-004 to T.L.); the Association for Frontotemporal Degeneration (no. 2019-0009 to Y.B. and T.L.); a Swiss National Science Foundation Postdoctoral Fellowship (no. P500PB_206890 to S.T.); and a Leverhulme Early Career Fellowship (no. ECF-2022-610 to D.A.). For the purposes of open access, the MRC Laboratory of Molecular Biology has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising.Frontotemporal lobar degeneration (FTLD) causes frontotemporal dementia (FTD), the most common form of dementia after Alzheimer's disease, and is often also associated with motor disorders1. The pathological hallmarks of FTLD are neuronal inclusions of specific, abnormally assembled proteins2. In the majority of cases the inclusions contain amyloid filament assemblies of TAR DNA-binding protein 43 (TDP-43) or tau, with distinct filament structures characterizing different FTLD subtypes3,4. The presence of amyloid filaments and their identities and structures in the remaining approximately 10% of FTLD cases are unknown but are widely believed to be composed of the protein fused in sarcoma (FUS, also known as translocated in liposarcoma). As such, these cases are commonly referred to as FTLD-FUS. Here we used cryogenic electron microscopy (cryo-EM) to determine the structures of amyloid filaments extracted from the prefrontal and temporal cortices of four individuals with FTLD-FUS. Surprisingly, we found abundant amyloid filaments of the FUS homologue TATA-binding protein-associated factor 15 (TAF15, also known as TATA-binding protein-associated factor 2N) rather than of FUS itself. The filament fold is formed from residues 7-99 in the low-complexity domain (LCD) of TAF15 and was identical between individuals. Furthermore, we found TAF15 filaments with the same fold in the motor cortex and brainstem of two of the individuals, both showing upper and lower motor neuron pathology. The formation of TAF15 amyloid filaments with a characteristic fold in FTLD establishes TAF15 proteinopathy in neurodegenerative disease. The structure of TAF15 amyloid filaments provides a basis for the development of model systems of neurodegenerative disease, as well as for the design of diagnostic and therapeutic tools targeting TAF15 proteinopathy