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Structure of pathological TDP-43 filaments from ALS with FTLD
Open accessAbstract
The abnormal aggregation of TAR DNA-binding protein 43 kDa (TDP-43) in neurons and glia is the defining pathological hallmark of the neurodegenerative disease amyotrophic lateral sclerosis (ALS) and multiple forms of frontotemporal lobar degeneration (FTLD)1,2. It is also common in other diseases, including Alzheimer’s and Parkinson’s. No disease-modifying therapies exist for these conditions and early diagnosis is not possible. The structures of pathological TDP-43 aggregates are unknown. Here we used cryo-electron microscopy to determine the structures of aggregated TDP-43 in the frontal and motor cortices of an individual who had ALS with FTLD and from the frontal cortex of a second individual with the same diagnosis. An identical amyloid-like filament structure comprising a single protofilament was found in both brain regions and individuals. The ordered filament core spans residues 282–360 in the TDP-43 low-complexity domain and adopts a previously undescribed double-spiral-shaped fold, which shows no similarity to those of TDP-43 filaments formed in vitro3,4. An abundance of glycine and neutral polar residues facilitates numerous turns and restricts β-strand length, which results in an absence of β-sheet stacking that is associated with cross-β amyloid structure. An uneven distribution of residues gives rise to structurally and chemically distinct surfaces that face external densities and suggest possible ligand-binding sites. This work enhances our understanding of the molecular pathogenesis of ALS and FTLD and informs the development of diagnostic and therapeutic agents that target aggregated TDP-43. Cryo-electron microscopy of aggregated TDP-43 from postmortem brain tissue of individuals who had ALS with FTLD reveals a filament structure with distinct features to other neuropathological protein filaments, such as those of tau and α-synuclein.
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Cites
Ubiquitinated TDP-43 in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis
Neumann, M., Sampathu, D. M., Kwong, L. K., Truax, A. C., Micsenyi, M. C., Chou, T. T., Bruce, J., Schuck, T., Grossman, M., Clark, C. M., et al. (2006) · Science · doi:10.1126/science.1134108 · Cited by 6,576
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Self-citationTDP-43 Mutations in Familial and Sporadic Amyotrophic Lateral Sclerosis
Sreedharan, J., Blair, I. P., Tripathi, V. B., Hu, X., Vance, C., Rogelj, B., Ackerley, S., Durnall, J. C., Williams, K. L., Buratti, E., et al. (2008) · Science · doi:10.1126/science.1154584 · Cited by 2,630
Structure-based classification of tauopathies
Shi, Y., Zhang, W., Yang, Y., Murzin, A. G., Falcon, B., Kotecha, A., van Beers, M., Tarutani, A., Kametani, F., Garringer, H. J., et al. (2021) · Nature · doi:10.1038/s41586-021-03911-7 · Cited by 878
Self-citationPhosphorylated TDP‐43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis
Hasegawa, M., Arai, T., Nonaka, T., Kametani, F., Yoshida, M., Hashizume, Y., Beach, T. G., Buratti, E., Baralle, F., Morita, M., et al. (2008) · Annals of Neurology · doi:10.1002/ana.21425 · Cited by 777
Self-citationAn autoradiographic evaluation of AV-1451 Tau PET in dementia
Lowe, V. J., Curran, G., Fang, P., Liesinger, A. M., Josephs, K. A., Parisi, J. E., Kantarci, K., Boeve, B. F., Pandey, M. K., Bruinsma, T., et al. (2016) · Acta Neuropathologica Communications · doi:10.1186/s40478-016-0315-6 · Cited by 474
Porta, S., Xu, Y., Restrepo, C. R., Kwong, L. K., Zhang, B., Brown, H. J., Lee, E. B., Trojanowski, J. Q., & Lee, V. M.-Y. (2018) · Nature Communications · doi:10.1038/s41467-018-06548-9 · Cited by 248
Taniguchi-Watanabe, S., Arai, T., Kametani, F., Nonaka, T., Masuda-Suzukake, M., Tarutani, A., Murayama, S., Saito, Y., Arima, K., Yoshida, M., et al. (2016) · Acta Neuropathologica · doi:10.1007/s00401-015-1503-3 · Cited by 200
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Cited by
Frontotemporal lobar degeneration
Grossman, M., Seeley, W. W., Boxer, A. L., Hillis, A. E., Knopman, D. S., Ljubenov, P. A., Miller, B., Piguet, O., Rademakers, R., Whitwell, J. L., et al. (2023) · Nature Reviews Disease Primers · doi:10.1038/s41572-023-00447-0 · Cited by 178
Homotypic fibrillization of TMEM106B across diverse neurodegenerative diseases
Chang, A., Xiang, X., Wang, J., Lee, C., Arakhamia, T., Simjanoska, M., Wang, C., Carlomagno, Y., Zhang, G., Dhingra, S., et al. (2022) · Cell · doi:10.1016/j.cell.2022.02.026 · Cited by 150
Short RNA chaperones promote aggregation-resistant TDP-43 conformers to mitigate neurodegeneration
Copley, K. E., Mauna, J. C., Danielson, H. L., Chen, Q., Ozguney, B., Ngo, M., Xie, L., Smirnov, A., Davis, M., Mayne, L., et al. (2026) · Science · doi:10.1126/science.adv3301 · Cited by 16
Protein kinase inhibitors as therapeutics in neurodegenerative and psychiatric disorders
Tridente, G., Jana, A., Nath, A., & Ashraf, G. M. (2023) · Receptor Tyrosine Kinases in Neurodegenerative and Psychiatric Disorders · doi:10.1016/b978-0-443-18677-6.00015-4 · Cited by 8
Jami, K. M., Corbett, K. E., Farb, D. C., Osumi, K. M., Shafer, C. C., Criscione, S., & Murray, D. T. (2026) · Biophysical Chemistry · doi:10.1016/j.bpc.2026.107590 · Cited by 2
Metadata
- Authors
- Arseni, D., Hasegawa, M., Murzin, A. G., Kametani, F., Arai, M., Yoshida, M., & Ryskeldi-Falcon, B.
- Venue
- Nature
- Published
- 2021-12-08
- Volume
- 601
- Issue
- 7891
- Pages
- 139-143
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W4200415658
- Cited by
- 305
- References
- 8
- FWCI
- 19.16
- Type
- journal article
- Language
- en
- Open access
- green
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