Acknowledgements: We thank the individuals and their families for donating brain tissue; the Manchester Brain Bank, which is part of the Brains for Dementia Research Initiative, jointly funded by the Alzheimer’s Society and Alzheimer’s Research UK, for supplying tissue from individuals 1 and 3; J. H. Grafman for supplying tissue from individual 4; the National Centralized Repository for Alzheimer’s Disease and Related Dementias, which receives funding from the National Institute on Aging, for supplying tissue from individual 5; the Center for Medical Genomics of Indiana University School of Medicine for next-generation DNA sequencing; M. H. Jacobsen for help with neuropathological examinations; R. Otani for help with immunolabelling; M. Tahira for help with mass spectrometry; K. Yamashita and G. Murshudov for help with Servalcat and model refinements in REFMAC5; staff at the MRC Laboratory of Molecular Biology Electron Microscopy Facility for access to and support with cryo-EM; staff at the MRC Laboratory of Molecular Biology Scientific Computing Facility for access to and support with computing; staff at the MRC Laboratory of Molecular Biology Mass Spectrometry Facility for access to and support with mass spectrometry; and T.S. Behr, A. Bertolotti, S.W. Davies, M. Goedert, S.H.W. Scheres and S. Tetter for discussions. This work was supported by the Medical Research Council, as part of UK Research and Innovation (MC_UP_1201/25 to B.R.-F.); an Alzheimer’s Research UK Rising Star Award (ARUK-RS2019-001 to B.R.-F.); the US National Institutes of Health (P30-AG010133, U01-NS110437 and RF1-AG071177 to R.V. and B.G); the Japan Agency for Medical Research and Development (JP20dm0207072 to M.H.); the Japan Science and Technology Agency Core Research for Evolutional Science and Technology (JPMJCR18H3 to M.H.); a Cambridge Commonwealth, European & International Trust Postgraduate Scholarship to R.C.; and a Leverhulme Early Career Fellowship (ECF-2022-610 to D.A.). For the purpose of open access, the MRC Laboratory of Molecular Biology has applied a CC BY public copyright licence to any author-accepted manuscript version arising.The abnormal assembly of TAR DNA-binding protein 43 (TDP-43) in neuronal and glial cells characterizes nearly all cases of amyotrophic lateral sclerosis (ALS) and around half of cases of frontotemporal lobar degeneration (FTLD)1, 2. A causal role for TDP-43 assembly in neurodegeneration is evidenced by dominantly inherited missense mutations in TARDBP, the gene encoding TDP-43, that promote assembly and give rise to ALS and FTLD3–7. At least four types (A–D) of FTLD with TDP-43 pathology (FTLD-TDP) are defined by distinct brain distributions of assembled TDP-43 and are associated with different clinical presentations of frontotemporal dementia8. We previously showed, using cryo-electron microscopy, that TDP-43 assembles into amyloid filaments in ALS and type B FTLD-TDP9. However, the structures of assembled TDP-43 in FTLD without ALS remained unknown. Here we report the cryo-electron microscopy structures of assembled TDP-43 from the brains of three individuals with the most common type of FTLD-TDP, type A. TDP-43 formed amyloid filaments with a new fold that was the same across individuals, indicating that this fold may characterize type A FTLD-TDP. The fold resembles a chevron badge and is unlike the double-spiral-shaped fold of ALS and type B FTLD-TDP, establishing that distinct filament folds of TDP-43 characterize different neurodegenerative conditions. The structures, in combination with mass spectrometry, led to the identification of two new post-translational modifications of assembled TDP-43, citrullination and monomethylation of R293, and indicate that they may facilitate filament formation and observed structural variation in individual filaments. The structures of TDP-43 filaments from type A FTLD-TDP will guide mechanistic studies of TDP-43 assembly, as well as the development of diagnostic and therapeutic compounds for TDP-43 proteinopathies
