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Quantifying subpercent nuclear TDP ‐43 loss in cells and ALS cortex using junction‐specific cryptic exon RT ‐ qPCR
Shingo Koide, Ichiko Ikegami, Ryutaro Hanyu, Yuka Mitsuhashi Koike, Takuma Yamagishi, Genri Toyama, Aya Washida, Mari Tada et al.. FEBS Letters, 2025-10-22
Topic: Brain proteins, microglia and lab models
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are progressive neurodegenerative diseases characterised by nuclear TDP-43 loss. Its hallmark, cryptic exon (CE) splicing, is often masked in bulk tissue analyses by the low abundance of affected neurons. We developed an ultrasensitive RT-qPCR assay targeting STMN2 CE using one exon-CE junction-spanning primer and the other within the CE. The design expands the dynamic range sevenfold: TDP-43 knockdown boosted STMN2 CE levels 1395-fold in differentiated SH-SY5Y neurons. Spike-in tests set detection at 0.16% deficient cells. Crucially, the assay revealed a 42-fold CE increase in ALS motor cortex, previously missed by conventional primers. This streamlined tool enables precise quantification of TDP-43 dysfunction and sensitive pharmacodynamic monitoring for future ALS-FTD therapeutic studies. Impact statement Because cryptic-exon signals are diluted in bulk tissue, we developed a junction-spanning STMN2 RT-qPCR with sub-percent sensitivity. This deployable biomarker will aid ALS/FTD researchers and drug developers by standardizing measurements and enabling sensitive pharmacodynamic monitoring of therapies targeting nuclear TDP-43 dysfunction.
Key findings
- Crucially, the assay revealed a 42-fold CE increase in ALS motor cortex, previously missed by conventional primers.
Why it matters
This study developed an ultrasensitive RT-qPCR assay targeting STMN2 cryptic exon that detected a 42-fold increase in ALS motor cortex previously missed by conventional primers, with detection set at 0.16% deficient cells. It is a measurement tool for research and drug studies and does not itself test any treatment, cure or prevention.
Study details
- Effect size0.16%
- Evidence strengthLow
How this study scored 35/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, 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 (FEBS Letters) |
| Journal's citation record | 3 / 4 | FEBS Letters: journal h-index 393 (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 | 2 / 3 | Effect reported as a number, without an interval or test |
| 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 | 1 / 7 | Cited 3 times (OpenAlex, 2026-10-10) |
| Citations per year | 1 / 5 | 1.0 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 2 / 6 | Cited 1.7× 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 3 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 1 / 4 | Last-listed author Akihiro Sugai: h-index 8 (OpenAlex, whole career) |
| Institution's track record | 0 / 3 | Niigata University: institution h-index 473 (OpenAlex) |
| Multi-centre collaboration | 0 / 3 | OpenAlex lists 1 institution(s) in 1 country — scores zero (affiliation lists can be incomplete) |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 41121980) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 35 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
May need a subscription OpenAlex found no free copy of the full text (checked 6 Feb 1020), so the publisher may charge for it. The PubMed abstract is free.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
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.
APA 7th
Koide, S., Ikegami, I., Hanyu, R., Koike, Y. M., Yamagishi, T., Toyama, G., et al. (2025). Quantifying subpercent nuclear TDP ‐43 loss in cells and ALS cortex using junction‐specific cryptic exon RT ‐ qPCR. FEBS Letters. https://doi.org/10.1002/1873-3468.70198
Vancouver
Koide S, Ikegami I, Hanyu R, Koike YM, Yamagishi T, Toyama G, et al. Quantifying subpercent nuclear TDP ‐43 loss in cells and ALS cortex using junction‐specific cryptic exon RT ‐ qPCR. FEBS Letters. 2025. doi:10.1002/1873-3468.70198. PMID: 41121980.
BibTeX
@article{koide2025-41121980,
author = {Koide, Shingo and Ikegami, Ichiko and Hanyu, Ryutaro and Koike, Yuka Mitsuhashi and Yamagishi, Takuma and Toyama, Genri and Washida, Aya and Tada, Mari and others},
title = {{Quantifying subpercent nuclear TDP ‐43 loss in cells and ALS cortex using junction‐specific cryptic exon RT ‐ qPCR}},
journal = {FEBS Letters},
year = {2025},
doi = {10.1002/1873-3468.70198},
pmid = {41121980},
url = {https://doi.org/10.1002/1873-3468.70198}
}
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