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Structure of pathological TDP-43 filaments from ALS with FTLD
Arseni D, Hasegawa M, Murzin AG, Kametani F, Arai M, Yoshida M, Ryskeldi-Falcon B.. Nature, 2021-12-08
Topic: Brain proteins, microglia and lab models
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 vitro 3,4 . 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.
Key findings
- 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.
Why it matters
Using cryo-electron microscopy on brain tissue from two people who had ALS with FTLD, this study described the shared filament structure of aggregated TDP-43. It is a structural study of tissue from a small number of individuals and does not test any treatment or prevention for Alzheimer's disease.
Study details
- Evidence strengthLow
How this study scored 58/100
Published in a top-tier journal. Scored zero for study design, sample size, effect reported and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 10 / 10 | Tier 1 — top-tier general journal (Nature) |
| Journal's citation record | 4 / 4 | Nature: journal h-index 1,841 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 3 / 5 | 2022 — within 6 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 3 / 3 | Studied in people (pubmed indexes it as a clinical or observational study) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 6 / 7 | Cited 307 times (OpenAlex, 2026-10-10) |
| Citations per year | 5 / 5 | 51.2 citations a year over 6 year(s) since 2022 |
| Impact for its field and year | 4 / 6 | Cited 19.3× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 3 / 6 | Cited by 11 other studies in this library |
| Still being cited | 3 / 4 | Cited 190 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Benjamin Falcon: h-index 25 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | MRC Laboratory of Molecular Biology: institution h-index 816 (OpenAlex) |
| Multi-centre collaboration | 1 / 3 | OpenAlex lists 3 institution(s) in 2 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 34880495) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 58 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
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Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record names 7 authors; APA and Vancouver show the first six, BibTeX and the downloads carry all of them. Check the citation against the original before you use it.
APA 7th
Arseni, D., Hasegawa, M., Murzin, A. G., Kametani, F., Arai, M., Yoshida, M., et al. (2022). Structure of pathological TDP-43 filaments from ALS with FTLD. Nature. https://doi.org/10.1038/s41586-021-04199-3
Vancouver
Arseni D, Hasegawa M, Murzin AG, Kametani F, Arai M, Yoshida M, et al. Structure of pathological TDP-43 filaments from ALS with FTLD. Nature. 2022. doi:10.1038/s41586-021-04199-3. PMID: 34880495.
BibTeX
@article{arseni2022-34880495,
author = {Arseni, D. and Hasegawa, M. and Murzin, A. G. and Kametani, F. and Arai, M. and Yoshida, M. and Ryskeldi-Falcon, B.},
title = {{Structure of pathological TDP-43 filaments from ALS with FTLD}},
journal = {Nature},
year = {2022},
doi = {10.1038/s41586-021-04199-3},
pmid = {34880495},
url = {https://doi.org/10.1038/s41586-021-04199-3}
}
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