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TDP-43 repression of nonconserved cryptic exons is compromised in ALS-FTD
Ling JP, Pletnikova O, Troncoso JC, Wong PC.. Science (New York, N.Y.), 2015-08-01
Topic: Brain proteins, microglia and lab models
Cytoplasmic aggregation of TDP-43, accompanied by its nuclear clearance, is a key common pathological hallmark of amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD). However, a limited understanding of this RNA-binding protein (RBP) impedes the clarification of pathogenic mechanisms underlying TDP-43 proteinopathy. In contrast to RBPs that regulate splicing of conserved exons, we found that TDP-43 repressed the splicing of nonconserved cryptic exons, maintaining intron integrity. When TDP-43 was depleted from mouse embryonic stem cells, these cryptic exons were spliced into messenger RNAs, often disrupting their translation and promoting nonsense-mediated decay. Moreover, enforced repression of cryptic exons prevented cell death in TDP-43-deficient cells. Furthermore, repression of cryptic exons was impaired in ALS-FTD cases, suggesting that this splicing defect could potentially underlie TDP-43 proteinopathy.
Key findings
- In contrast to RBPs that regulate splicing of conserved exons, we found that TDP-43 repressed the splicing of nonconserved cryptic exons, maintaining intron integrity.
- Furthermore, repression of cryptic exons was impaired in ALS-FTD cases, suggesting that this splicing defect could potentially underlie TDP-43 proteinopathy.
Why it matters
In mouse embryonic stem cells, loss of TDP-43 caused nonconserved cryptic exons to be spliced into messenger RNAs, often disrupting their translation, and forcing repression of these exons prevented cell death in TDP-43-deficient cells. Repression of cryptic exons was also impaired in ALS-FTD cases, suggesting this splicing defect could potentially underlie TDP-43 proteinopathy.
Study details
- Evidence strengthLow
How this study scored 57/100
Published in a top-tier 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 | 10 / 10 | Tier 1 — top-tier general journal (Science (New York, N.Y.)) |
| Journal's citation record | 4 / 4 | Science: journal h-index 1,754 (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 | 2015 — 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 695 times (OpenAlex, 2026-10-10) |
| Citations per year | 5 / 5 | 53.5 citations a year over 13 year(s) since 2015 |
| Impact for its field and year | 5 / 6 | Cited 23.2× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 3 / 6 | Cited by 28 other studies in this library |
| Still being cited | 4 / 4 | Cited 312 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author Philip C. Wong: h-index 71 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | Johns Hopkins University: institution h-index 2,306 (OpenAlex) |
| Multi-centre collaboration | 1 / 3 | OpenAlex lists 2 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 26250685) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 57 / 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
Ling, J. P., Pletnikova, O., Troncoso, J. C., & Wong, P. C. (2015). TDP-43 repression of nonconserved cryptic exons is compromised in ALS-FTD. Science (New York, N.Y.). https://doi.org/10.1126/science.aab0983
Vancouver
Ling JP, Pletnikova O, Troncoso JC, Wong PC. TDP-43 repression of nonconserved cryptic exons is compromised in ALS-FTD. Science (New York, N.Y.). 2015. doi:10.1126/science.aab0983. PMID: 26250685.
BibTeX
@article{ling2015-26250685,
author = {Ling, J. P. and Pletnikova, O. and Troncoso, J. C. and Wong, P. C.},
title = {{TDP-43 repression of nonconserved cryptic exons is compromised in ALS-FTD}},
journal = {Science (New York, N.Y.)},
year = {2015},
doi = {10.1126/science.aab0983},
pmid = {26250685},
url = {https://doi.org/10.1126/science.aab0983}
}
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