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TDP ‐43 proteinopathies and neurodegeneration: insights from Caenorhabditis elegans models
Ghulam Jeelani Pir, Joerg Buddenkotte, Majid Ali Alam, Ahmed M. Own, Randall J. Eck, Brian C. Kraemer, Eckhard Mandelkow�, Martin S. Steinhoff. FEBS Journal, 2025-09-02
Topic: Brain proteins, microglia and lab models
TDP-linked proteinopathies, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and limbic-predominant age-related TDP-43 encephalopathy (LATE), are characterised by pathogenic deposits containing transactive response DNA-binding protein 43 (TDP-43) in the brain and spinal cord of patients. These hallmark pathological features are associated with widespread neuronal dysfunction and progressive neurodegeneration. TDP-43's role as an essential RNA/DNA-binding protein in RNA metabolism and gene expression regulation is clear, but deciphering the intricate pathophysiological mechanisms underpinning TDP-43-mediated neurodegeneration is paramount for developing effective therapies and novel diagnostic tools for early detection before frank neuronal loss occurs. The nematode Caenorhabditis elegans, with highly conserved TDP-43 orthologue TDP-1, serves as a powerful genetic model to investigate the molecular underpinnings of TDP-43 proteinopathies. Here, we provide a brief overview of the structural and functional characteristics of TDP-43 and TDP-1, highlighting their conserved roles in RNA metabolism, stress responses, and neurodegeneration. We then delve into the pathobiology of TDP-43, drawing insights from C. elegans models expressing either monogenic TDP-43 variants or bigenic combinations with ALS-associated risk genes, and discuss how these models have advanced our understanding of the pathomechanisms of TDP-43 proteinopathies. By employing its simplicity and genetic manipulability, we discuss how these models have helped identify chemical and genetic suppressors of TDP-43-induced phenotypes, including small molecules like Pimozide and the probiotic Lacticaseibacillus rhamnosus HA-114, now in clinical trials. This review underscores the translational value of C. elegans in unraveling the biochemical pathways and interactions in TDP-43 proteinopathies that perturb cellular physiology, potentially facilitating mechanism-based therapy development.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Pir, G. J., Buddenkotte, J., Alam, M. A., Own, A. M., Eck, R. J., Kraemer, B. C., et al. (2025). TDP ‐43 proteinopathies and neurodegeneration: insights from Caenorhabditis elegans models. FEBS Journal. https://doi.org/10.1111/febs.70239
Vancouver
Pir GJ, Buddenkotte J, Alam MA, Own AM, Eck RJ, Kraemer BC, et al. TDP ‐43 proteinopathies and neurodegeneration: insights from Caenorhabditis elegans models. FEBS Journal. 2025. doi:10.1111/febs.70239. PMID: 40891506.
BibTeX
@article{pir2025-40891506,
author = {Pir, Ghulam Jeelani and Buddenkotte, Joerg and Alam, Majid Ali and Own, Ahmed M. and Eck, Randall J. and Kraemer, Brian C. and Mandelkow�, Eckhard and Steinhoff, Martin S.},
title = {{TDP ‐43 proteinopathies and neurodegeneration: insights from Caenorhabditis elegans models}},
journal = {FEBS Journal},
year = {2025},
doi = {10.1111/febs.70239},
pmid = {40891506},
url = {https://doi.org/10.1111/febs.70239}
}
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 8 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.
Key findings
- These hallmark pathological features are associated with widespread neuronal dysfunction and progressive neurodegeneration.
Why it matters
This review discusses how the nematode Caenorhabditis elegans and its conserved TDP-43 orthologue TDP-1 are used as a genetic model to study the molecular mechanisms of TDP-43 proteinopathies. It is a review of research models and does not report or test any treatment, cure or prevention.
Study details
- Evidence strengthLow
How this study scored 43/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported and randomized / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (FEBS Journal) |
| Journal's citation record | 2 / 4 | FEBS Journal: journal h-index 225 (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 | 4 / 5 | 2025 — within 3 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 | Laboratory or animal study (title names “caenorhabditis”) — scores zero |
| Randomized / blinded | 0 / 2 | No randomization or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 2 / 7 | Cited 5 times (OpenAlex, 2026-10-10) |
| Citations per year | 1 / 5 | 1.7 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 2 / 6 | Cited 2.8× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 1 / 4 | Cited 5 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author Martin S. Steinhoff: h-index 92 (OpenAlex, whole career) |
| Institution's track record | 3 / 3 | University of Washington: institution h-index 3,540 (OpenAlex) |
| Multicenter collaboration | 3 / 3 | OpenAlex lists 10 institution(s) in 3 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40891506) |
| Free to read | 2 / 2 | Free to read |
| Total | 43 / 100 | — |
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Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
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