Neumann, M. et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314, 130–133 (2006).
Google Scholar
Arai, T. et al. TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem. Biophys. Res. Commun. 351, 602–611 (2006).
Google Scholar
Sreedharan, J. et al. TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319, 1668–1672 (2008).
Google Scholar
Kabashi, E. et al. TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat. Genet. 40, 572–574 (2008).
Google Scholar
Van Deerlin, V. M. et al. TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis. Lancet Neurol. 7, 409–416 (2008).
Google Scholar
Borroni, B. et al. Mutation within TARDBP leads to frontotemporal dementia without motor neuron disease. Hum. Mutat. 30, E974–E983 (2009).
Google Scholar
Kovacs, G. G. et al. TARDBP variation associated with frontotemporal dementia, supranuclear gaze palsy, and chorea. Mov. Disord. 24, 1842–1847 (2009).
Google Scholar
Mackenzie, I. R. A. et al. A harmonized classification system for FTLD-TDP pathology. Acta Neuropathol. 122, 111–113 (2011).
Google Scholar
Arseni, D. et al. Structure of pathological TDP-43 filaments from ALS with FTLD. Nature 601, 139–143 (2022).
Google Scholar
Ayala, Y. M. et al. Structural determinants of the cellular localization and shuttling of TDP-43. J. Cell Sci. 121, 3778–3785 (2008).
Google Scholar
Afroz, T. et al. Functional and dynamic polymerization of the ALS-linked protein TDP-43 antagonizes its pathologic aggregation. Nat. Commun. 8, 45 (2017).
Google Scholar
Hasegawa, M. et al. Phosphorylated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Ann. Neurol. 64, 60–70 (2008).
Google Scholar
Lin, W.-L. & Dickson, D. W. Ultrastructural localization of TDP-43 in filamentous neuronal inclusions in various neurodegenerative diseases. Acta Neuropathol. 116, 205–213 (2008).
Google Scholar
Mori, F. et al. Maturation process of TDP-43-positive neuronal cytoplasmic inclusions in amyotrophic lateral sclerosis with and without dementia. Acta Neuropathol. 116, 193–203 (2008).
Google Scholar
Thorpe, J. R., Tang, H., Atherton, J. & Cairns, N. J. Fine structural analysis of the neuronal inclusions of frontotemporal lobar degeneration with TDP-43 proteinopathy. J. Neural Transm. 115, 1661–1671 (2008).
Google Scholar
Nishihira, Y. et al. Sporadic amyotrophic lateral sclerosis: two pathological patterns shown by analysis of distribution of TDP-43-immunoreactive neuronal and glial cytoplasmic inclusions. Acta Neuropathol. 116, 169–182 (2008).
Google Scholar
Nonaka, T. et al. Prion-like properties of pathological TDP-43 aggregates from diseased brains. Cell Rep. 4, 124–134 (2013).
Google Scholar
Cracco, L. et al. Distinguishing post-translational modifications in dominantly inherited frontotemporal dementias: FTLD-TDP type A (GRN) vs type B (C9orf72). Neuropathol. Appl. Neurobiol. 48, e12836 (2022).
Google Scholar
Tarutani, A. et al. Ultrastructural and biochemical classification of pathogenic tau, α-synuclein and TDP-43. Acta Neuropathol. 143, 613–640 (2022).
Google Scholar
Robinson, J. L. et al. TDP-43 skeins show properties of amyloid in a subset of ALS cases. Acta Neuropathol. 125, 121–131 (2013).
Google Scholar
Jiang, Y. X. et al. Amyloid fibrils in FTLD-TDP are composed of TMEM106B and not TDP-43. Nature 605, 304–309 (2022).
Google Scholar
Schweighauser, M. et al. Age-dependent formation of TMEM106B amyloid filaments in human brains. Nature 605, 310–314 (2022).
Google Scholar
Chang, A. et al. Homotypic fibrillization of TMEM106B across diverse neurodegenerative diseases. Cell 185, 1346–1355.e15 (2022).
Google Scholar
Fan, Y. et al. Generic amyloid fibrillation of TMEM106B in patient with Parkinson’s disease dementia and normal elders. Cell Res. 32, 585–588 (2022).
Google Scholar
Hoq, Md. R. et al. Cross-β helical filaments of tau and TMEM106B in gray and white matter of multiple system tauopathy with presenile dementia. Acta Neuropathol. 145, 707–710 (2023).
Google Scholar
Baker, M. et al. Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 442, 916–919 (2006).
Google Scholar
Cruts, M. et al. Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature 442, 920–924 (2006).
Google Scholar
Perneel, J. et al. Accumulation of TMEM106B C-terminal fragments in neurodegenerative disease and aging. Acta Neuropathol. 145, 285–302 (2022).
Google Scholar
Vicente, C. T. et al. C-terminal TMEM106B fragments in human brain correlate with disease-associated TMEM106B haplotypes. Brain https://doi.org/10.1093/brain/awad133 (2023).
Kametani, F. et al. Mass spectrometric analysis of accumulated TDP-43 in amyotrophic lateral sclerosis brains. Sci. Rep. 6, 23281 (2016).
Google Scholar
Ulamec, S. M., Brockwell, D. J. & Radford, S. E. Looking beyond the core: the role of flanking regions in the aggregation of amyloidogenic peptides and proteins. Front. Neurosci. 14, 611285 (2020).
Google Scholar
Yang, Y. et al. Structures of α-synuclein filaments from human brains with Lewy pathology. Nature 610, 791–795 (2022).
Google Scholar
Falcon, B. et al. Novel tau filament fold in chronic traumatic encephalopathy encloses hydrophobic molecules. Nature 568, 420–423 (2019).
Google Scholar
Schweighauser, M. et al. Structures of α-synuclein filaments from multiple system atrophy. Nature 585, 464–469 (2020).
Google Scholar
Radamaker, L. et al. Cryo-EM reveals structural breaks in a patient-derived amyloid fibril from systemic AL amyloidosis. Nat. Commun. 12, 875 (2021).
Google Scholar
Guo, A. et al. Immunoaffinity enrichment and mass spectrometry analysis of protein methylation. Mol. Cell. Proteomics 13, 372–387 (2014).
Google Scholar
Aikio, M. et al. Opposing roles of p38α-mediated phosphorylation and arginine methylation in driving TDP-43 proteinopathy. Preprint at bioRxiv https://doi.org/10.1101/2021.08.04.455154 (2021).
Blanc, R. S. & Richard, S. Arginine methylation: the coming of age. Mol. Cell 65, 8–24 (2017).
Google Scholar
Tanikawa, C. et al. Citrullination of RGG motifs in FET proteins by PAD4 regulates protein aggregation and ALS susceptibility. Cell Rep. 22, 1473–1483 (2018).
Google Scholar
Mondal, S. & Thompson, P. R. Chemical biology of protein citrullination by the protein A arginine deiminases. Curr. Opin. Chem. Biol. 63, 19–27 (2021).
Google Scholar
Shi, Y. et al. Structure-based classification of tauopathies. Nature 598, 359–363 (2021).
Google Scholar
Tsuji, H. et al. Molecular analysis and biochemical classification of TDP-43 proteinopathy. Brain 135, 3380–3391 (2012).
Google Scholar
Kato, M. et al. Cell-free formation of RNA granules: low complexity sequence domains form dynamic fibers within hydrogels. Cell 149, 753–767 (2012).
Google Scholar
Conicella, A. E., Zerze, G. H., Mittal, J. & Fawzi, N. L. ALS mutations disrupt phase separation mediated by α-helical structure in the TDP-43 low-complexity C-terminal domain. Structure 24, 1537–1549 (2016).
Google Scholar
Knight, A. C. et al. Head-to-head comparison of Tau-PET radioligands for imaging TDP-43 in post-mortem ALS brain. Mol. Imaging Biol. 25, 513–527 (2023).
Google Scholar
Laferrière, F. et al. TDP-43 extracted from frontotemporal lobar degeneration subject brains displays distinct aggregate assemblies and neurotoxic effects reflecting disease progression rates. Nat. Neurosci. 22, 65 (2019).
Google Scholar
De Rossi, P. et al. FTLD-TDP assemblies seed neoaggregates with subtype-specific features via a prion-like cascade. EMBO Rep. 22, e53877 (2021).
Google Scholar
Porta, S. et al. Patient-derived frontotemporal lobar degeneration brain extracts induce formation and spreading of TDP-43 pathology in vivo. Nat. Commun. 9, 4220 (2018).
Google Scholar
Cao, Q., Boyer, D. R., Sawaya, M. R., Ge, P. & Eisenberg, D. S. Cryo-EM structures of four polymorphic TDP-43 amyloid cores. Nat. Struct. Mol. Biol. 26, 619–627 (2019).
Google Scholar
Li, Q., Babinchak, W. M. & Surewicz, W. K. Cryo-EM structure of amyloid fibrils formed by the entire low complexity domain of TDP-43. Nat. Commun. 12, 1620 (2021).
Google Scholar
Kumar, S. T. et al. Seeding the aggregation of TDP-43 requires post-fibrillization proteolytic cleavage. Nat. Neurosci. 26, 983–996 (2023).
Google Scholar
Huey, E. D. et al. Characteristics of frontotemporal dementia patients with a Progranulin mutation. Ann. Neurol. 60, 374–380 (2006).
Google Scholar
Renton, A. E. et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72, 257–268 (2011).
Google Scholar
Spina, S. et al. Clinicopathologic features of frontotemporal dementia with Progranulin sequence variation. Neurology 68, 820–827 (2007).
Google Scholar
Zivanov, J., Nakane, T. & Scheres, S. H. W. A Bayesian approach to beam-induced motion correction in cryo-EM single-particle analysis. IUCrJ 6, 5–17 (2019).
Google Scholar
Rohou, A. & Grigorieff, N. CTFFIND4: fast and accurate defocus estimation from electron micrographs. J. Struct. Biol. 192, 216–221 (2015).
Google Scholar
He, S. & Scheres, S. H. W. Helical reconstruction in RELION. J. Struct. Biol. 198, 163–176 (2017).
Google Scholar
Kimanius, D., Dong, L., Sharov, G., Nakane, T. & Scheres, S. H. W. New tools for automated cryo-EM single-particle analysis in RELION-4.0. Biochem. J. 478, 4169–4185 (2021).
Google Scholar
Scheres, S. H. W. Amyloid structure determination in RELION -3.1. Acta Crystallogr. D Struct. Biol. 76, 94–101 (2020).
Google Scholar
Zivanov, J., Nakane, T. & Scheres, S. H. W. Estimation of high-order aberrations and anisotropic magnification from cryo-EM data sets in RELION-3.1. IUCrJ 7, 253–267 (2020).
Google Scholar
Chen, S. et al. High-resolution noise substitution to measure overfitting and validate resolution in 3D structure determination by single particle electron cryomicroscopy. Ultramicroscopy 135, 24–35 (2013).
Google Scholar
Casañal, A., Lohkamp, B. & Emsley, P. Current developments in Coot for macromolecular model building of electron cryo-microscopy and crystallographic data. Protein Sci. 29, 1055–1064 (2020).
Google Scholar
Croll, T. I. ISOLDE: a physically realistic environment for model building into low-resolution electron-density maps. Acta Crystallogr. D Struct. Biol. 74, 519–530 (2018).
Google Scholar
Brown, A. et al. Tools for macromolecular model building and refinement into electron cryo-microscopy reconstructions. Acta Crystallogr. D Struct. Biol. 71, 136–153 (2015).
Google Scholar
Yamashita, K., Palmer, C. M., Burnley, T. & Murshudov, G. N. Cryo-EM single-particle structure refinement and map calculation using Servalcat. Acta Crystallogr. D Struct. Biol. 77, 1282–1291 (2021).
Google Scholar
Williams, C. J. et al. MolProbity: more and better reference data for improved all-atom structure validation. Protein Sci. 27, 293–315 (2018).
Google Scholar
Pettersen, E. F. et al. UCSF ChimeraX: structure visualization for researchers, educators, and developers. Protein Sci. 30, 70–82 (2021).
Google Scholar