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Aberrant cleavage of TDP-43 enhances aggregation and cellular toxicity
Zhang YJ, Xu YF, Cook C, Gendron TF, Roettges P, Link CD, Lin WL, Tong J et al.. Proceedings of the National Academy of Sciences of the United States of America, 2009-04-21
Topic: Brain proteins, microglia and lab models
Inclusions of TAR DNA-binding protein-43 (TDP-43), a nuclear protein that regulates transcription and RNA splicing, are the defining histopathological feature of frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-Us) and sporadic and familial forms of amyotrophic lateral sclerosis (ALS). In ALS and FTLD-U, aggregated, ubiquitinated, and N-terminally truncated TDP-43 can be isolated from brain tissue rich in neuronal and glial cytoplasmic inclusions. The loss of TDP-43 function resulting from inappropriate cleavage, translocation from the nucleus, or its sequestration into inclusions could play important roles in neurodegeneration. However, it is not known whether TDP-43 fragments directly mediate toxicity and, more specifically, whether their abnormal aggregation is a cause or consequence of pathogenesis. We report that the ectopic expression of a approximately 25-kDa TDP-43 fragment corresponding to the C-terminal truncation product of caspase-cleaved TDP-43 leads to the formation of toxic, insoluble, and ubiquitin- and phospho-positive cytoplasmic inclusions within cells. The 25-kDa C-terminal fragment is more prone to phosphorylation at S409/S410 than full-length TDP-43, but phosphorylation at these sites is not required for inclusion formation or toxicity. Although this fragment shows no biological activity, its exogenous expression neither inhibits the function nor causes the sequestration of full-length nuclear TDP-43, suggesting that the 25-kDa fragment can induce cell death through a toxic gain-of-function. Finally, by generating a conformation-dependent antibody that detects C-terminal fragments, we show that this toxic cleavage product is specific for pathologic inclusions in human TDP-43 proteinopathies.
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APA 7th
Zhang, Y. J., Xu, Y. F., Cook, C., Gendron, T. F., Roettges, P., Link, C. D., et al. (2009). Aberrant cleavage of TDP-43 enhances aggregation and cellular toxicity. Proceedings of the National Academy of Sciences of the United States of America. https://doi.org/10.1073/pnas.0900688106
Vancouver
Zhang YJ, Xu YF, Cook C, Gendron TF, Roettges P, Link CD, et al. Aberrant cleavage of TDP-43 enhances aggregation and cellular toxicity. Proceedings of the National Academy of Sciences of the United States of America. 2009. doi:10.1073/pnas.0900688106. PMID: 19383787.
BibTeX
@article{zhang2009-19383787,
author = {Zhang, Y. J. and Xu, Y. F. and Cook, C. and Gendron, T. F. and Roettges, P. and Link, C. D. and Lin, W. L. and Tong, J. and others},
title = {{Aberrant cleavage of TDP-43 enhances aggregation and cellular toxicity}},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
year = {2009},
doi = {10.1073/pnas.0900688106},
pmid = {19383787},
url = {https://doi.org/10.1073/pnas.0900688106}
}
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Key findings
- Although this fragment shows no biological activity, its exogenous expression neither inhibits the function nor causes the sequestration of full-length nuclear TDP-43, suggesting that the 25-kDa fragment can induce cell death through a toxic gain-of-function.
Why it matters
In cells, a roughly 25-kDa piece of the protein TDP-43, the fragment left when the enzyme caspase cuts it, formed toxic, insoluble clumps. The study suggests it kills cells by a new toxic effect ("gain of function") rather than by disabling normal TDP-43, and phosphorylation was not needed for that. The authors also report that this fragment is found specifically in the abnormal protein clumps of human TDP-43 diseases such as FTLD-U and ALS. This is laboratory work on ALS and frontotemporal lobar degeneration, not Alzheimer's, and it does not test any treatment.
Study details
- Evidence strengthLow
How this study scored 55/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomized / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Proceedings of the National Academy of Sciences of the United States of America) |
| Journal's citation record | 4 / 4 | Proceedings of the National Academy of Sciences: journal h-index 1,167 (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 | 1 / 5 | 2009 — within 20 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 | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomized / blinded | 0 / 2 | No randomization or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 6 / 7 | Cited 606 times (OpenAlex, 2026-10-10) |
| Citations per year | 4 / 5 | 31.9 citations a year over 19 year(s) since 2009 |
| Impact for its field and year | 5 / 6 | Cited 27.4× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 4 / 6 | Cited by 40 other studies in this library |
| Still being cited | 3 / 4 | Cited 77 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 4 / 4 | Last-listed author Leonard Petrucelli: h-index 112 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | Mayo Clinic: institution h-index 1,606 (OpenAlex) |
| Multicenter collaboration | 2 / 3 | OpenAlex lists 7 institution(s) in 4 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 19383787) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 55 / 100 | — |
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