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RNA Binding Antagonizes Neurotoxic Phase Transitions of TDP-43
Mann JR, Gleixner AM, Mauna JC, Gomes E, DeChellis-Marks MR, Needham PG, Copley KE, Hurtle B et al.. Neuron, 2019-02-27
Topic: Brain proteins, microglia and lab models
Plain-language summary
TDP-43 proteinopathy is a pathological hallmark of amyotrophic lateral sclerosis and frontotemporal dementia where cytoplasmic TDP-43 inclusions are observed within degenerating regions of patient postmortem tissue. The mechanism by which TDP-43 aggregates has remained elusive due to technological limitations, which prevent the analysis of specific TDP-43 interactions in live cells. We present an optogenetic approach to reliably induce TDP-43 proteinopathy under spatiotemporal control. We show that the formation of pathologically relevant inclusions is driven by aberrant interactions between low-complexity domains of TDP-43 that are antagonized by RNA binding. Although stress granules are hypothesized to be a conduit for seeding TDP-43 proteinopathy, we demonstrate pathological inclusions outside these RNA-rich structures. Furthermore, we show that aberrant phase transitions of cytoplasmic TDP-43 are neurotoxic and that treatment with oligonucleotides composed of TDP-43 target sequences prevent inclusions and rescue neurotoxicity. Collectively, these studies provide insight into the mechanisms that underlie TDP-43 proteinopathy and present a potential avenue for therapeutic intervention.
What this study adds
Evidence grade: Low
Using an optogenetic cell model, this study found that TDP-43 inclusions form through interactions between low-complexity domains that RNA binding can oppose, and that oligonucleotides matching TDP-43 target sequences prevented inclusions and rescued toxicity. These are laboratory findings and not yet a treatment for patients.
Taken from this record’s own fields, not from reading the paper. The grade is assigned from the abstract’s wording; what that means.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Mann, JR., Gleixner, A. M., Mauna, J. C., Gomes, E., DeChellis-Marks, M. R., Needham, P. G., et al. (2019). RNA Binding Antagonizes Neurotoxic Phase Transitions of TDP-43. Neuron. https://doi.org/10.1016/j.neuron.2019.01.048
Vancouver
Mann JR, Gleixner AM, Mauna JC, Gomes E, DeChellis-Marks MR, Needham PG, et al. RNA Binding Antagonizes Neurotoxic Phase Transitions of TDP-43. Neuron. 2019. doi:10.1016/j.neuron.2019.01.048. PMID: 30826182.
BibTeX
@article{mann2019-30826182,
author = {Mann, JR. and Gleixner, A. M. and Mauna, J. C. and Gomes, E. and DeChellis-Marks, M. R. and Needham, P. G. and Copley, K. E. and Hurtle, B. and others},
title = {{RNA Binding Antagonizes Neurotoxic Phase Transitions of TDP-43}},
journal = {Neuron},
year = {2019},
doi = {10.1016/j.neuron.2019.01.048},
pmid = {30826182},
url = {https://doi.org/10.1016/j.neuron.2019.01.048}
}
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's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
Key findings
- We present an optogenetic approach to reliably induce TDP-43 proteinopathy under spatiotemporal control.
- We show that the formation of pathologically relevant inclusions is driven by aberrant interactions between low-complexity domains of TDP-43 that are antagonized by RNA binding.
- Although stress granules are hypothesized to be a conduit for seeding TDP-43 proteinopathy, we demonstrate pathological inclusions outside these RNA-rich structures.
- Furthermore, we show that aberrant phase transitions of cytoplasmic TDP-43 are neurotoxic and that treatment with oligonucleotides composed of TDP-43 target sequences prevent inclusions and rescue neurotoxicity.
- Collectively, these studies provide insight into the mechanisms that underlie TDP-43 proteinopathy and present a potential avenue for therapeutic intervention.
Why it matters
Using an optogenetic cell model, this study found that TDP-43 inclusions form through interactions between low-complexity domains that RNA binding can oppose, and that oligonucleotides matching TDP-43 target sequences prevented inclusions and rescued toxicity. These are laboratory findings and not yet a treatment for patients.
Study details
- Evidence strengthLow
How this study scored 53/100
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 (Neuron) |
| Journal's citation record | 4 / 4 | Neuron: journal h-index 689 (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 | 2 / 5 | 2019 — within 10 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 541 times (OpenAlex, 2026-10-10) |
| Citations per year | 5 / 5 | 60.1 citations a year over 9 year(s) since 2019 |
| Impact for its field and year | 5 / 6 | Cited 38.7× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 3 / 6 | Cited by 16 other studies in this library |
| Still being cited | 3 / 4 | Cited 192 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Christopher J. Donnelly: h-index 28 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | University of Pennsylvania: institution h-index 1,859 (OpenAlex) |
| Multicenter collaboration | 1 / 3 | OpenAlex lists 3 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 30826182) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 53 / 100 | — |
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