TDP-43 dysfunction induces cryptic circular RNAs in ALS/FTD
- 1UCL Queen Square Motor Neuron Disease Centre, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, UCL, London, UK; The Francis Crick
Abstract
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.
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BibTeX
@misc{dattilo2026tdp43,
title = {{TDP-43 dysfunction induces cryptic circular RNAs in ALS/FTD}},
author = {D. Dattilo and F. Pellegrini and S. Barattucci and A.-L. Brown and J. N. S. Vargas and A. Gatt and R. Morrie and G. Miller and I. Bachmutsky and Z. McEachin and M. Chung and M. J. Keuss and E. Ryadnov and M. Zanovello and P. R. Mehta and F. Mattedi and M. Barioglio and S. Kamath and S. E. Kargbo-Hill and J. Palade and I. Kowal and J. Glass and M. Gearing and E. B. Lee and M. E. Murray and D. W. Dickson and NYGC ALS Consortium and E. M. Green and N. T. Seyfried and S. Chandriani and M. Ward and P. Fratta},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.17.752342},
url = {https://www.biorxiv.org/content/10.64898/2026.09.17.752342v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - TDP-43 dysfunction induces cryptic circular RNAs in ALS/FTD
AU - D. Dattilo
AU - F. Pellegrini
AU - S. Barattucci
AU - A.-L. Brown
AU - J. N. S. Vargas
AU - A. Gatt
AU - R. Morrie
AU - G. Miller
AU - I. Bachmutsky
AU - Z. McEachin
AU - M. Chung
AU - M. J. Keuss
AU - E. Ryadnov
AU - M. Zanovello
AU - P. R. Mehta
AU - F. Mattedi
AU - M. Barioglio
AU - S. Kamath
AU - S. E. Kargbo-Hill
AU - J. Palade
AU - I. Kowal
AU - J. Glass
AU - M. Gearing
AU - E. B. Lee
AU - M. E. Murray
AU - D. W. Dickson
AU - NYGC ALS Consortium
AU - E. M. Green
AU - N. T. Seyfried
AU - S. Chandriani
AU - M. Ward
AU - P. Fratta
PY - 2026
DA - 2026/09/17
PB - bioRxiv
DO - 10.64898/2026.09.17.752342
UR - https://www.biorxiv.org/content/10.64898/2026.09.17.752342v1
AB - 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.
ER -