{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T19:39:25Z","timestamp":1787168365862,"version":"build-2736575974"},"posted":{"date-parts":[[2026,1,12]]},"group-title":"Molecular Biology","reference-count":66,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T00:00:00Z","timestamp":1768176000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Medical Research Council","award":["MC_UP_1201\/25"],"award-info":[{"award-number":["MC_UP_1201\/25"]}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01-NS137469"],"award-info":[{"award-number":["R01-NS137469"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01-NS110437"],"award-info":[{"award-number":["R01-NS110437"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["UAG063911"],"award-info":[{"award-number":["UAG063911"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["P30-AG010133"],"award-info":[{"award-number":["P30-AG010133"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["RF1-AG071177"],"award-info":[{"award-number":["RF1-AG071177"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01-AG080001"],"award-info":[{"award-number":["R01-AG080001"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000320","name":"Alzheimer's Society","doi-asserted-by":"crossref","award":["AS-PG-18-004"],"award-info":[{"award-number":["AS-PG-18-004"]}],"id":[{"id":"10.13039\/501100000320","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000320","name":"Alzheimer's Society","doi-asserted-by":"crossref","award":["AS-PG-21-004"],"award-info":[{"award-number":["AS-PG-21-004"]}],"id":[{"id":"10.13039\/501100000320","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100003607","name":"Association for Frontotemporal Degeneration","doi-asserted-by":"crossref","award":["2019-0009"],"award-info":[{"award-number":["2019-0009"]}],"id":[{"id":"10.13039\/100003607","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001711","name":"Swiss National Science Foundation","doi-asserted-by":"crossref","award":["P500PB_206890"],"award-info":[{"award-number":["P500PB_206890"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,1,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Neurodegenerative diseases are characterised by the assembly of a limited number of disease-specific proteins into amyloid filaments, which form intracellular inclusions or extracellular deposits in the central nervous system (CNS)\n                  <jats:sup>1,2<\/jats:sup>\n                  . We previously found that amyloid filaments of TATA-binding protein-associated factor 15 (TAF15) characterise a subtype of frontotemporal lobar degeneration with FET protein-immunoreactive inclusions (FTLD-FET)\n                  <jats:sup>3<\/jats:sup>\n                  , termed atypical FTLD with ubiquitin-positive inclusions (aFTLD-U)\n                  <jats:sup>4<\/jats:sup>\n                  , which causes early-onset, rapidly progressive behavioural variant frontotemporal dementia (FTD). However, it was not clear if TAF15 proteinopathy was more widespread in neurodegenerative diseases. Two additional FTLD-FET subtypes have been proposed, neuronal intermediate filament inclusion body disease (NIFID) and basophilic inclusion body disease (BIBD)\n                  <jats:sup>5,6<\/jats:sup>\n                  , which have more heterogenous clinical presentations including FTD, motor neuron diseases (MND) and movement disorders. Here, we used electron cryo-microscopy (cryo-EM) to determine a total of 32 amyloid filament structures from the brains of 17 individuals encompassing all three proposed subtypes of FTLD-FET and their diverse clinical presentations. All cases were characterised by TAF15 filaments, in the absence of filaments of the other FET proteins, fused in sarcoma (FUS) and Ewing\u2019s sarcoma (EWS). All three aFTLD-U cases had the previously-reported TAF15 fold\n                  <jats:sup>3<\/jats:sup>\n                  . Unexpectedly, we found four distinct TAF15 folds among 11 NIFID cases. Eight of these cases shared a common fold, while the remaining three were each distinct. Furthermore, we found distinct TAF15 folds for each of the three BIBD cases. Neuropathological reassessment of the neocortical TAF15 inclusion pathology of these cases distinguished the NIFID cases with the common fold from the others. Thus, TAF15 filament structures form the basis of a new, expanded classification of FTLD-FET subtypes. Moreover, we discovered a TAF15 Y38C variant in the filament fold of one of the individuals with BIBD. The structure is unable to incorporate wild-type TAF15, despite the individual being heterozygous, suggesting that this variant drives TAF15 filament assembly. This study provides structural and genetic evidence that TAF15 amyloid filaments underlie the diverse group of neurodegenerative diseases currently termed FTLD-FET, which we therefore rename FTLD-TAF15.\n                <\/jats:p>","DOI":"10.64898\/2026.01.12.698957","type":"posted-content","created":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T02:05:17Z","timestamp":1768269917000},"source":"Crossref","is-referenced-by-count":2,"title":["Distinct TAF15 amyloid filament folds define multiple subtypes of FTLD-TAF15"],"prefix":"10.64898","author":[{"given":"Stephan","family":"Tetter","sequence":"first","affiliation":[{"name":"MRC Laboratory of Molecular Biology, Cambridge, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikhil R.","family":"Varghese","sequence":"additional","affiliation":[{"name":"MRC Laboratory of Molecular Biology, Cambridge, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexey G.","family":"Murzin","sequence":"additional","affiliation":[{"name":"MRC Laboratory of Molecular Biology, Cambridge, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5248-8197","authenticated-orcid":false,"given":"Wouter","family":"De Coster","sequence":"additional","affiliation":[{"name":"VIB Center for Molecular Neurology, Antwerp, Belgium"},{"name":"University of Antwerp, Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marleen","family":"Van den Broeck","sequence":"additional","affiliation":[{"name":"VIB Center for Molecular Neurology, Antwerp, Belgium"},{"name":"University of Antwerp, Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sigrun","family":"Roeber","sequence":"additional","affiliation":[{"name":"Center for Neuropathology and Prion Research, Ludwig-Maximilians-Universit\u00e4t, Munich, Germany"},{"name":"Munich Cluster for Systems Neurology (Synergy), Munich, Germany"},{"name":"German Center for Neurodegenerative Diseases (DZNE), Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey T.","family":"Joseph","sequence":"additional","affiliation":[{"name":"University of Calgary, Calgary, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathy","family":"Newell","sequence":"additional","affiliation":[{"name":"Indiana University School of Medicine, Indianapolis, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rudolf","family":"Castellani","sequence":"additional","affiliation":[{"name":"Northwestern University, Illinois, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sumit","family":"Das","sequence":"additional","affiliation":[{"name":"University of Alberta, Edmonton, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lee-Cyn","family":"Ang","sequence":"additional","affiliation":[{"name":"Western University, London, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2280-7273","authenticated-orcid":false,"given":"Matthis","family":"Synofzik","sequence":"additional","affiliation":[{"name":"Division of Translational Genomics of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research and Center of Neurology, University of T\u00fcbingen, Germany"},{"name":"German Center for Neurodegenerative Diseases (DZNE), T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jochen","family":"Herms","sequence":"additional","affiliation":[{"name":"Center for Neuropathology and Prion Research, Ludwig-Maximilians-Universit\u00e4t, Munich, Germany"},{"name":"Munich Cluster for Systems Neurology (Synergy), Munich, Germany"},{"name":"German Center for Neurodegenerative Diseases (DZNE), Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosa","family":"Rademakers","sequence":"additional","affiliation":[{"name":"VIB Center for Molecular Neurology, Antwerp, Belgium"},{"name":"University of Antwerp, Antwerp, Belgium"},{"name":"Mayo Clinic, Jacksonville, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernardino","family":"Ghetti","sequence":"additional","affiliation":[{"name":"Indiana University School of Medicine, Indianapolis, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tammaryn","family":"Lashley","sequence":"additional","affiliation":[{"name":"University College London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian R. A.","family":"Mackenzie","sequence":"additional","affiliation":[{"name":"University of British Columbia, Vancouver, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuela","family":"Neumann","sequence":"additional","affiliation":[{"name":"German Center for Neurodegenerative Diseases (DZNE), T\u00fcbingen, Germany"},{"name":"Department of Neuropathology, University Hospital of T\u00fcbingen, T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8176-2618","authenticated-orcid":false,"given":"Benjamin","family":"Ryskeldi-Falcon","sequence":"additional","affiliation":[{"name":"MRC Laboratory of Molecular Biology, Cambridge, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026020420434183000_2026.01.12.698957v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2022.12.032"},{"key":"2026020420434183000_2026.01.12.698957v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06437-2"},{"key":"2026020420434183000_2026.01.12.698957v1.3","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06801-2"},{"key":"2026020420434183000_2026.01.12.698957v1.4","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awp214"},{"key":"2026020420434183000_2026.01.12.698957v1.5","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-009-0581-5"},{"key":"2026020420434183000_2026.01.12.698957v1.6","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-009-0598-9"},{"key":"2026020420434183000_2026.01.12.698957v1.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.08.013"},{"key":"2026020420434183000_2026.01.12.698957v1.8","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1986.tb04288.x"},{"key":"2026020420434183000_2026.01.12.698957v1.9","doi-asserted-by":"crossref","unstructured":"Radamaker, L. et al. Cryo-EM reveals structural breaks in a patient-derived amyloid fibril from systemic AL amyloidosis. Nat Commun 12, 875 (2021).","DOI":"10.1038\/s41467-021-21126-2"},{"key":"2026020420434183000_2026.01.12.698957v1.10","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06405-w"},{"key":"2026020420434183000_2026.01.12.698957v1.11","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.85.13.4884"},{"key":"2026020420434183000_2026.01.12.698957v1.12","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.7.3590"},{"key":"2026020420434183000_2026.01.12.698957v1.13","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biochem-060614-034325"},{"key":"2026020420434183000_2026.01.12.698957v1.14","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awr201"},{"key":"2026020420434183000_2026.01.12.698957v1.15","doi-asserted-by":"publisher","DOI":"10.1111\/nan.12526"},{"key":"2026020420434183000_2026.01.12.698957v1.16","doi-asserted-by":"publisher","DOI":"10.1126\/science.1166066"},{"key":"2026020420434183000_2026.01.12.698957v1.17","doi-asserted-by":"publisher","DOI":"10.1126\/science.1165942"},{"key":"2026020420434183000_2026.01.12.698957v1.18","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-010-0764-0"},{"key":"2026020420434183000_2026.01.12.698957v1.19","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1007\/BF00293404","article-title":"A case of Pick\u2019s disease with unusual neuronal inclusions","volume":"88","year":"1994","journal-title":"Acta Neuropathol"},{"key":"2026020420434183000_2026.01.12.698957v1.20","doi-asserted-by":"publisher","DOI":"10.1016\/S0304-3940(03)00100-9"},{"key":"2026020420434183000_2026.01.12.698957v1.21","doi-asserted-by":"publisher","DOI":"10.1001\/archneur.1972.00490160028004"},{"key":"2026020420434183000_2026.01.12.698957v1.22","doi-asserted-by":"publisher","DOI":"10.1007\/BF00691069"},{"key":"2026020420434183000_2026.01.12.698957v1.23","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awr160"},{"key":"2026020420434183000_2026.01.12.698957v1.24","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsb.2017.02.003"},{"key":"2026020420434183000_2026.01.12.698957v1.25","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-34552-7"},{"key":"2026020420434183000_2026.01.12.698957v1.26","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1038\/s41467-023-43822-x","article-title":"Cryo-EM structures of lipidic fibrils of amyloid-\u03b2 (1-40)","volume":"15","year":"2024","journal-title":"Nat Commun"},{"key":"2026020420434183000_2026.01.12.698957v1.27","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-008-0460-5"},{"key":"2026020420434183000_2026.01.12.698957v1.28","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-011-0863-6"},{"key":"2026020420434183000_2026.01.12.698957v1.29","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-012-1020-6"},{"key":"2026020420434183000_2026.01.12.698957v1.30","doi-asserted-by":"publisher","DOI":"10.1038\/362059a0"},{"key":"2026020420434183000_2026.01.12.698957v1.31","doi-asserted-by":"publisher","DOI":"10.1126\/science.1134108"},{"key":"2026020420434183000_2026.01.12.698957v1.32","first-page":"1597","article-title":"TDP-43 seeding induces cytoplasmic aggregation heterogeneity and nuclear loss of function of TDP-43","volume":"10","year":"2025","journal-title":"Neuron"},{"key":"2026020420434183000_2026.01.12.698957v1.33","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2025.03.008"},{"key":"2026020420434183000_2026.01.12.698957v1.34","doi-asserted-by":"publisher","DOI":"10.1126\/science.aab0983"},{"key":"2026020420434183000_2026.01.12.698957v1.35","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1016\/j.celrep.2013.01.021","article-title":"Identification of In Vivo, Conserved, TAF15 RNA Binding Sites Reveals the Impact of TAF15 on the Neuronal Transcriptome","volume":"3","year":"2013","journal-title":"Cell Reports"},{"key":"2026020420434183000_2026.01.12.698957v1.36","doi-asserted-by":"publisher","DOI":"10.1006\/geno.1996.0591"},{"key":"2026020420434183000_2026.01.12.698957v1.37","doi-asserted-by":"publisher","DOI":"10.1016\/S0378-1119(98)00463-6"},{"key":"2026020420434183000_2026.01.12.698957v1.38","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1996.tb00882.x"},{"key":"2026020420434183000_2026.01.12.698957v1.39","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03911-7"},{"key":"2026020420434183000_2026.01.12.698957v1.40","doi-asserted-by":"publisher","DOI":"10.1101\/2025.11.17.688886"},{"key":"2026020420434183000_2026.01.12.698957v1.41","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-021-02294-3"},{"key":"2026020420434183000_2026.01.12.698957v1.42","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-38537-y"},{"key":"2026020420434183000_2026.01.12.698957v1.43","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2023.168025"},{"key":"2026020420434183000_2026.01.12.698957v1.44","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-52265-x"},{"key":"2026020420434183000_2026.01.12.698957v1.45","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2206240119"},{"key":"2026020420434183000_2026.01.12.698957v1.46","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-32951-4"},{"key":"2026020420434183000_2026.01.12.698957v1.47","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.b.31158"},{"key":"2026020420434183000_2026.01.12.698957v1.48","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1109434108"},{"key":"2026020420434183000_2026.01.12.698957v1.49","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awad120"},{"key":"2026020420434183000_2026.01.12.698957v1.50","doi-asserted-by":"crossref","unstructured":"Neumann, M. & Mackenzie, I. R. FUS\/FET proteinopathies. in Greenfield\u2019s Neuropathology 10e Set (CRC Press, 2024).","DOI":"10.1201\/9781003389699-36"},{"key":"2026020420434183000_2026.01.12.698957v1.51","doi-asserted-by":"publisher","DOI":"10.48550\/arXiv.1303.3997"},{"key":"2026020420434183000_2026.01.12.698957v1.52","doi-asserted-by":"publisher","DOI":"10.1101\/201178"},{"key":"2026020420434183000_2026.01.12.698957v1.53","doi-asserted-by":"publisher","DOI":"10.1093\/gigascience\/giab008"},{"key":"2026020420434183000_2026.01.12.698957v1.54","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-016-0974-4"},{"key":"2026020420434183000_2026.01.12.698957v1.55","doi-asserted-by":"publisher","DOI":"10.1107\/S205225251801463X"},{"key":"2026020420434183000_2026.01.12.698957v1.56","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsb.2015.08.008"},{"key":"2026020420434183000_2026.01.12.698957v1.57","doi-asserted-by":"publisher","DOI":"10.1042\/BCJ20210708"},{"key":"2026020420434183000_2026.01.12.698957v1.58","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1107\/S2059798319016577","article-title":"Amyloid structure determination in RELION \u20133.1","volume":"76","year":"2020","journal-title":"Acta Crystallogr D Struct Biol"},{"key":"2026020420434183000_2026.01.12.698957v1.59","doi-asserted-by":"publisher","DOI":"10.1107\/S2052252520000081"},{"key":"2026020420434183000_2026.01.12.698957v1.60","doi-asserted-by":"publisher","DOI":"10.1016\/j.ultramic.2013.06.004"},{"key":"2026020420434183000_2026.01.12.698957v1.61","doi-asserted-by":"publisher","DOI":"10.1002\/pro.3791"},{"key":"2026020420434183000_2026.01.12.698957v1.62","doi-asserted-by":"publisher","DOI":"10.1107\/S2059798318002425"},{"key":"2026020420434183000_2026.01.12.698957v1.63","doi-asserted-by":"publisher","DOI":"10.1107\/S1399004714021683"},{"key":"2026020420434183000_2026.01.12.698957v1.64","doi-asserted-by":"publisher","DOI":"10.1107\/S2059798321009475"},{"key":"2026020420434183000_2026.01.12.698957v1.65","doi-asserted-by":"publisher","DOI":"10.1107\/S2059798319011471"},{"key":"2026020420434183000_2026.01.12.698957v1.66","doi-asserted-by":"publisher","DOI":"10.1002\/pro.3330"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.01.12.698957","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T04:43:52Z","timestamp":1770266632000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.01.12.698957"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,12]]},"references-count":66,"URL":"https:\/\/doi.org\/10.64898\/2026.01.12.698957","relation":{},"subject":[],"published":{"date-parts":[[2026,1,12]]},"subtype":"preprint"}}