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Structural determinants of the cellular localization and shuttling of TDP-43
Ayala YM, Zago P, D'Ambrogio A, Xu YF, Petrucelli L, Buratti E, Baralle FE.. Journal of cell science, 2008-10-28
Topic: Brain proteins, microglia and lab models
TDP-43 (also known as TARDBP) regulates different processes of gene expression, including transcription and splicing, through RNA and DNA binding. Moreover, recent reports have shown that the protein interacts with the 3'UTRs of specific mRNAs. The aberrant cellular distribution and aggregation of TDP-43 were recently reported in neurodegenerative diseases, namely frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). A detailed description of the determinants for cellular localization has yet to emerge, including information on how the known functions of TDP-43 and cellular targeting affect each other. We provide the first experimental evidence that TDP-43 continuously shuttles between nucleus and cytoplasm in a transcription-dependent manner. Furthermore, we investigate the role of the functional TDP-43 domains in determining cellular targeting through a combination of immunofluorescence and biochemical fractionation methods. Our analyses indicate that the C-terminus is essential for solubility and cellular localization, because its deletion results in the formation of large nuclear and cytoplasmic aggregates. Disruption of the RNA-recognition domain required for RNA and DNA binding, however, alters nuclear distribution by decreasing TDP-43 presence in the nucleoplasm. Our findings suggest that TDP-43 solubility and localization are particularly sensitive to disruptions that extend beyond the newly found nuclear localization signal and depend on a combination of factors that are closely connected to the functional properties of this protein.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Ayala, Y. M., Zago, P., D'Ambrogio, A., Xu, Y. F., Petrucelli, L., Buratti, E., et al. (2008). Structural determinants of the cellular localization and shuttling of TDP-43. Journal of cell science. https://doi.org/10.1242/jcs.038950
Vancouver
Ayala YM, Zago P, D'Ambrogio A, Xu YF, Petrucelli L, Buratti E, et al. Structural determinants of the cellular localization and shuttling of TDP-43. Journal of cell science. 2008. doi:10.1242/jcs.038950. PMID: 18957508.
BibTeX
@article{ayala2008-18957508,
author = {Ayala, Y. M. and Zago, P. and D'Ambrogio, A. and Xu, Y. F. and Petrucelli, L. and Buratti, E. and Baralle, F. E.},
title = {{Structural determinants of the cellular localization and shuttling of TDP-43}},
journal = {Journal of cell science},
year = {2008},
doi = {10.1242/jcs.038950},
pmid = {18957508},
url = {https://doi.org/10.1242/jcs.038950}
}
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.
Key findings
- Moreover, recent reports have shown that the protein interacts with the 3'UTRs of specific mRNAs.
- Our analyses indicate that the C-terminus is essential for solubility and cellular localization, because its deletion results in the formation of large nuclear and cytoplasmic aggregates.
- Our findings suggest that TDP-43 solubility and localization are particularly sensitive to disruptions that extend beyond the newly found nuclear localization signal and depend on a combination of factors that are closely connected to the functional properties of this protein.
Why it matters
In lab experiments, the authors report "the first experimental evidence that TDP-43 continuously shuttles between nucleus and cytoplasm in a transcription-dependent manner", and found that removing the protein's C-terminus produced "large nuclear and cytoplasmic aggregates", while disrupting its RNA-binding domain reduced its presence in the nucleoplasm. The abnormal placement and clumping of TDP-43 that this work set out to explain is linked in the study to frontotemporal lobar degeneration (FTLD) and ALS. The study does not mention Alzheimer's, includes no patients, and tests no treatment.
Study details
- Evidence strengthLow
How this study scored 51/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Journal of cell science) |
| Journal's citation record | 3 / 4 | Journal of Cell Science: journal h-index 385 (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 | 2008 — 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) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 6 / 7 | Cited 635 times (OpenAlex, 2026-10-10) |
| Citations per year | 4 / 5 | 31.8 citations a year over 20 year(s) since 2008 |
| Impact for its field and year | 4 / 6 | Cited 15.5× 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 128 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author Francisco Ernesto Baralle: h-index 80 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | Mayo Clinic: institution h-index 1,606 (OpenAlex) |
| Multi-centre collaboration | 1 / 3 | OpenAlex lists 3 institution(s) in 2 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 18957508) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 51 / 100 | — |
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