TDP-43 dysfunction induces cryptic circular RNAs in ALS/FTD
Dattilo D, Pellegrini F, Barattucci S, Brown A, Vargas JNS, Gatt A, Morrie R, Miller G et al.. bioRxiv, 2026-09-20
Topic: Genetics and APOE
Nuclear depletion of TDP-43 is a defining pathological feature of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), leading to widespread RNA misprocessing, including the formation of cryptic exons. Here, we identified TDP-43 as a regulator of circular RNA (circRNA) biogenesis in multiple human neuronal cell models, and showed that its dysfunction induces the de novo formation of cryptic circular RNAs (c-circRNAs). Analysis of post-mortem brain transcriptomic data identified a subset of c-circRNAs which are specific for ALS and FTD cases with TDP-43 pathology. Further, we developed highly sensitive rolling-circle amplification-based circRNA detection assays that allow to distinguish TDP-43 pathology in human CNS tissues with a 0.99 AUC. We found that c-circRNAs can co-occur with cryptic linear splicing events, uncovering complex RNA misprocessing hotspots that induce loss of disease-relevant proteins, including RPTOR and EHMT1 . Notably, one of these c-circRNAs originates from UNC13A , a gene whose cryptic exon has previously been linked to one of the major GWAS hits in ALS/FTD and that is being pursued as a therapeutic target through splice-switching ASOs. We showed that c-circUNC13A is co-regulated with the linear cryptic transcript and suppression of UNC13A cryptic exon results in c-circUNC13A reduction in cultured neurons and in vivo, highlighting its potential as a target engagement biomarker for emerging UNC13A-directed therapies. Overall, this work identifies a novel molecular mechanism for TDP-43 dysfunction, opening novel avenues for understanding disease pathogenesis and developing much needed pathology biomarkers.
Key findings
- Here, we identified TDP-43 as a regulator of circular RNA (circRNA) biogenesis in multiple human neuronal cell models, and showed that its dysfunction induces the de novo formation of cryptic circular RNAs (c-circRNAs).
- We found that c-circRNAs can co-occur with cryptic linear splicing events, uncovering complex RNA misprocessing hotspots that induce loss of disease-relevant proteins, including RPTOR and EHMT1 .
- We showed that c-circUNC13A is co-regulated with the linear cryptic transcript and suppression of UNC13A cryptic exon results in c-circUNC13A reduction in cultured neurons and in vivo, highlighting its potential as a target engagement biomarker for emerging UNC13A-directed therapies.
- Overall, this work identifies a novel molecular mechanism for TDP-43 dysfunction, opening novel avenues for understanding disease pathogenesis and developing much needed pathology biomarkers.
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Study details
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 21 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it. We have no data on times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multi-centre collaboration, so those were left out: it earned 13 of the 62 points we could judge it on, which is 21 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (bioRxiv) |
| Journal's citation record | 0 / 4 | Not a journal article, so the journal's record does not count |
| 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 | 4 / 10 | Preprint — not yet peer-reviewed. Hosted on a preprint server. |
| How recent | 5 / 5 | 2026 — within 1 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 | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 13 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 13 of the 62 points we could judge it on is 21 out of 100. |
| Total | 21 / 100 | Capped to 16 because this is not a peer-reviewed article. |
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APA 7th
Dattilo, D., Pellegrini, F., Barattucci, S., Brown, A., Vargas, J. N. S., Gatt, A., et al. (2026). TDP-43 dysfunction induces cryptic circular RNAs in ALS/FTD. bioRxiv. https://doi.org/10.64898/2026.09.17.752342
Vancouver
Dattilo D, Pellegrini F, Barattucci S, Brown A, Vargas JNS, Gatt A, et al. TDP-43 dysfunction induces cryptic circular RNAs in ALS/FTD. bioRxiv. 2026. doi:10.64898/2026.09.17.752342.
BibTeX
@article{dattilo2026-13f2bc93,
author = {Dattilo, D. and Pellegrini, F. and Barattucci, S. and Brown, A. and Vargas, J. N. S. and Gatt, A. and Morrie, R. and Miller, G. and others},
title = {{TDP-43 dysfunction induces cryptic circular RNAs in ALS/FTD}},
journal = {bioRxiv},
year = {2026},
doi = {10.64898/2026.09.17.752342},
url = {https://doi.org/10.64898/2026.09.17.752342}
}