Distinct TAF15 amyloid filament folds define multiple subtypes of FTLD-TAF15
Year: 2026
Type: preprint
Abstract: ABSTRACT 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) 1,2 . 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) 3 , termed atypical FTLD with ubiquitin-positive inclusions (aFTLD-U) 4 , 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) 5,6 , 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’s sarcoma (EWS). All three aFTLD-U cases had the previously-reported TAF15 fold 3 . 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.
Authors: Stephan Tetter, Nikhil R. Varghese, Alexey G. Murzin, Wouter De Coster, Marleen Van den Broeck, Sigrun Roeber, Jeffrey T. Joseph, Kathy Newell, Rudolf Castellani, Sumit Das, Lee-Cyn Ang, Matthis Synofzik, Jochen Herms, Rosa Rademakers, Bernardino Ghetti, Tammaryn Lashley, Ian R. A. Mackenzie, Manuela Neumann, Benjamin Ryskeldi-Falcon
Institutions: MRC Laboratory of Molecular Biology, University of Antwerp, VIB-UAntwerp Center for Molecular Neurology, German Center for Neurodegenerative Diseases, Munich Cluster for Systems Neurology, Institut für Neuropathologie, Ludwig-Maximilians-Universität München, University of Calgary, Indiana University School of Medicine, Northwestern University, University of Alberta, Western University, Hertie Institute for Clinical Brain Research, University of Tübingen, Mayo Clinic in Florida, University College London, University of British Columbia, Universitätsklinikum Tübingen
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Association for Frontotemporal Degeneration, Alzheimer's Society, University College London, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Deutsches Zentrum für Neurodegenerative Erkrankungen, National Institutes of Health, School of Medicine, Indiana University, Medical Research Council, National Institute on Aging, Reta Lila Weston Institute of Neurological Studies, UCL Queen Square Institute of Neurology,University College London
Awards: Indiana Alzheimer Disease Center, Structural investigation of TDP-43 aggregation, G3129114953, G3266925675, Structural analysis of tau associated with parenchymal and vascular prion protein amyloidosis, Investigating the role of TDP-43 mislocalization, structure, and post-translational modifications in the neuropathologically heterogeneous TDP-43 proteinopathies, G6157042684, G9000061021, G9000102514, G9000178104, ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration, Cycle 2 (ALLFTD2), Indiana Alzheimer's Disease Research Center, Structural analysis of tau associated with parenchymal and vascular prion protein amyloidosis, Identification of novel four repeat tauopathies through analysis of network vulnerability, tau structure and propagation.
OpenAlex ID: W7123356890