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Disease-linked TDP-43 hyperphosphorylation suppresses TDP-43 condensation and aggregation
Gruijs da Silva LA, Simonetti F, Hutten S, Riemenschneider H, Sternburg EL, Pietrek LM, Gebel J, Dötsch V et al.. The EMBO journal, 2022-02-03
Topic: Brain proteins, microglia and lab models
Post-translational modifications (PTMs) have emerged as key modulators of protein phase separation and have been linked to protein aggregation in neurodegenerative disorders. The major aggregating protein in amyotrophic lateral sclerosis and frontotemporal dementia, the RNA-binding protein TAR DNA-binding protein (TDP-43), is hyperphosphorylated in disease on several C-terminal serine residues, a process generally believed to promote TDP-43 aggregation. Here, we however find that Casein kinase 1δ-mediated TDP-43 hyperphosphorylation or C-terminal phosphomimetic mutations reduce TDP-43 phase separation and aggregation, and instead render TDP-43 condensates more liquid-like and dynamic.
Key findings
- The major aggregating protein in amyotrophic lateral sclerosis and frontotemporal dementia, the RNA-binding protein TAR DNA-binding protein (TDP-43), is hyperphosphorylated in disease on several C-terminal serine residues, a process generally believed to promote TDP-43 aggregation.
- Here, we however find that Casein kinase 1δ-mediated TDP-43 hyperphosphorylation or C-terminal phosphomimetic mutations reduce TDP-43 phase separation and aggregation, and instead render TDP-43 condensates more liquid-like and dynamic.
- Multi-scale molecular dynamics simulations reveal reduced homotypic interactions of TDP-43 low-complexity domains through enhanced solvation of phosphomimetic residues.
- Cellular experiments show that phosphomimetic substitutions do not affect nuclear import or RNA regulatory functions of TDP-43, but suppress accumulation of TDP-43 in membrane-less organelles and promote its solubility in neurons.
Why it matters
This laboratory work found that Casein kinase 1delta-mediated TDP-43 hyperphosphorylation or C-terminal phosphomimetic mutations reduced TDP-43 phase separation and aggregation, making condensates more liquid-like and dynamic, contrary to the usual assumption. It is early mechanistic research on TDP-43 in ALS and frontotemporal dementia and does not address treating, curing or preventing Alzheimer's disease.
Study details
- Evidence strengthLow
How this study scored 52/100
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 (The EMBO journal) |
| Journal's citation record | 4 / 4 | The EMBO Journal: journal h-index 563 (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 | 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 | 5 / 7 | Cited 202 times (OpenAlex, 2026-10-10) |
| Citations per year | 4 / 5 | 33.7 citations a year over 6 year(s) since 2022 |
| Impact for its field and year | 4 / 6 | Cited 19.4× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 2 / 6 | Cited by 9 other studies in this library |
| Still being cited | 3 / 4 | Cited 132 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Dorothee Dormann: h-index 33 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | Goethe University Frankfurt: institution h-index 958 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 6 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 35112738) |
| Free to read | 2 / 2 | Free to read |
| Total | 52 / 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
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APA 7th
Gruijs da Silva, L. A., Simonetti, F., Hutten, S., Riemenschneider, H., Sternburg, E. L., Pietrek, L. M., et al. (2022). Disease-linked TDP-43 hyperphosphorylation suppresses TDP-43 condensation and aggregation. The EMBO journal. https://doi.org/10.15252/embj.2021108443
Vancouver
Gruijs da Silva LA, Simonetti F, Hutten S, Riemenschneider H, Sternburg EL, Pietrek LM, et al. Disease-linked TDP-43 hyperphosphorylation suppresses TDP-43 condensation and aggregation. The EMBO journal. 2022. doi:10.15252/embj.2021108443. PMID: 35112738.
BibTeX
@article{gruijsdasilva2022-35112738,
author = {Gruijs da Silva, L. A. and Simonetti, F. and Hutten, S. and Riemenschneider, H. and Sternburg, E. L. and Pietrek, L. M. and Gebel, J. and Dötsch, V. and others},
title = {{Disease-linked TDP-43 hyperphosphorylation suppresses TDP-43 condensation and aggregation}},
journal = {The EMBO journal},
year = {2022},
doi = {10.15252/embj.2021108443},
pmid = {35112738},
url = {https://doi.org/10.15252/embj.2021108443}
}
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