---
title: "TDP-43 dysfunction drives formation of cryptic circular RNAs in ALS and FTD"
id: "biorxiv-5-tdp-43-dysfunction-induces-cryptic-circular-rnas-in-als-ftd"
canonical_url: "https://medichelpline.com/clinical-feed/biorxiv-5-tdp-43-dysfunction-induces-cryptic-circular-rnas-in-als-ftd"
content_type: "clinical_feed_article"
specialty: "Neurology"
source_name: "bioRxiv (Biomedical Preprints)"
source_url: "https://www.biorxiv.org/content/10.64898/2026.09.17.752342v1?rss=1"
published_at: "2026-09-20T12:00:00.000Z"
evidence_level: "Verified Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# TDP-43 dysfunction drives formation of cryptic circular RNAs in ALS and FTD
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/biorxiv-5-tdp-43-dysfunction-induces-cryptic-circular-rnas-in-als-ftd
- **Specialty:** [Neurology](https://medichelpline.com/clinical-feed/neurology.md)
- **Primary Source:** bioRxiv (Biomedical Preprints)
- **Source URL:** [Original Journal Publication](https://www.biorxiv.org/content/10.64898/2026.09.17.752342v1?rss=1)
- **Published At:** 2026-09-20T12:00:00.000Z
- **Evidence Rating:** Verified Feed
## Executive GIST (TL;DR)
- Nuclear loss of **TDP-43** is a hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) and causes widespread RNA misprocessing, including cryptic exons and now cryptic circular RNAs. - The study identifies **TDP-43** as a regulator of circular RNA (**circRNA**) biogenesis in multiple human neuronal cell models; TDP-43 dysfunction induces de novo formation of **cryptic circular RNAs (c-circRNAs)**. - Analysis of post-mortem brain transcriptomes revealed a subset of c-circRNAs that are specific to ALS/FTD cases with TDP-43 pathology. - The authors developed highly sensitive **rolling-circle amplification**–based assays for circRNA detection that discriminate TDP-43 pathology in human CNS tissues with an area under the curve (AUC) of 0.99. - c-circRNAs can co-occur with cryptic linear splicing events, defining RNA misprocessing hotspots associated with loss of disease-relevant proteins such as **RPTOR** and **EHMT1**. - One identified c-circRNA originates from **UNC13A**, a gene with a previously described cryptic exon linked to a major GWAS signal in ALS/FTD and targeted by splice-switching antisense oligonucleotide (ASO) therapies. - Suppressing the UNC13A cryptic exon reduces production of the UNC13A-derived c-circRNA in cultured neurons and in vivo, suggesting potential use of c-circUNC13A as a target-engagement biomarker for UNC13A-directed therapies. - The work proposes a novel molecular mechanism for TDP-43 dysfunction and introduces new avenues for understanding pathogenesis and developing pathology biomarkers for ALS/FTD. - Competing interests: PF, DD and FP filed a patent related to TDP-43 circRNAs; PF is founder/advisor/shareholder of Trace Neuroscience Inc.; MJK consults for and holds shares in Trace Neuroscience Inc.
## Clinical Analysis & Structured Key Points
TDP-43 dysfunction induces cryptic circular RNAs in ALS/FTD | bioRxiv Skip to main content New Results TDP-43 dysfunction induces cryptic circular RNAs in ALS/FTD Dario Dattilo , Flaminia Pellegrini , Simone Barattucci , Anna-Leigh Brown , Jose Norberto S. Vargas , Ariana Gatt , Ryan Morrie , Georgiana Miller , Iris Bachmutsky , Zachary McEachin , Mingee Chung , Matthew J. Keuss , Eugeni Ryadnov , Matteo Zanovello , Puja R. Mehta , Francesca Mattedi , Michela Barioglio , Shubha Kamath , Sarah E Kargbo-Hill , Joanna Palade , Isabelle Kowal , Jonathan Glass , Marla Gearing , Edward B Lee , Melissa E Murray , Dennis W Dickson , NYGC ALS Consortium , Eric M Green , Nicholas T Seyfried , Sanjay Chandriani , Michael Ward , Pietro Fratta doi: https://doi.org/10.64898/2026.09.17.752342 Dario Dattilo 1 UCL Queen Square Motor Neuron Disease Centre, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, UCL, London, UK; The Francis Crick Institute, London, UK; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Flaminia Pellegrini 1 UCL Queen Square Motor Neuron Disease Centre, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, UCL, London, UK; The Francis Crick Institute, London, UK; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Simone Barattucci 2 UCL Queen Square Motor Neuron Disease Centre, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, UCL, London, UK; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Anna-Leigh Brown 2 UCL Queen Square Motor Neuron Disease Centre, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, UCL, London, UK; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Jose Norberto S. Vargas 2 UCL Queen Square Motor Neuron Disease Centre, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, UCL, London, UK; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Ariana Gatt 3 Department of Neurodegenerative Disease, Institute of Neurology, University College London, London, UK; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Ryan Morrie 4 Trace Neuroscience, South San Francisco, CA 94080, USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Georgiana Miller 4 Trace Neuroscience, South San Francisco, CA 94080, USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Iris Bachmutsky 4 Trace Neuroscience, South San Francisco, CA 94080, USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Zachary McEachin 5 Center for Neurodegenerative Disease, Emory University, Atlanta, GA 30329, USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Mingee Chung 5 Center for Neurodegenerative Disease, Emory University, Atlanta, GA 30329, USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Matthew J. Keuss 2 UCL Queen Square Motor Neuron Disease Centre, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, UCL, London, UK; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Eugeni Ryadnov 2 UCL Queen Square Motor Neuron Disease Centre, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, UCL, London, UK; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Matteo Zanovello 2 UCL Queen Square Motor Neuron Disease Centre, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, UCL, London, UK; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Puja R. Mehta 2 UCL Queen Square Motor Neuron Disease Centre, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, UCL, London, UK; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Francesca Mattedi 2 UCL Queen Square Motor Neuron Disease Centre, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, UCL, London, UK; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Michela Barioglio 2 UCL Queen Square Motor Neuron Disease Centre, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, UCL, London, UK; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Shubha Kamath 2 UCL Queen Square Motor Neuron Disease Centre, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, UCL, London, UK; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Sarah E Kargbo-Hill 6 Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI, USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Joanna Palade 7 National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Isabelle Kowal 7 National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Jonathan Glass 8 Departments of Neurology and Pathology, Emory University, Atlanta, GA, USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Marla Gearing 9 Department of Pathology and Laboratory Medicine, Department of Neurology, Goizueta Alzheimer's Disease Research Center, Emory University, Atlanta, GA, USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Edward B Lee 10 Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Melissa E Murray 11 Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Dennis W Dickson 11 Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Eric M Green 4 Trace Neuroscience, South San Francisco, CA 94080, USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Nicholas T Seyfried 5 Center for Neurodegenerative Disease, Emory University, Atlanta, GA 30329, USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Sanjay Chandriani 4 Trace Neuroscience, South San Francisco, CA 94080, USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Michael Ward 7 National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Pietro Fratta 1 UCL Queen Square Motor Neuron Disease Centre, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, UCL, London, UK; The Francis Crick Institute, London, UK; Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: p.fratta{at}ucl.ac.uk Abstract Info/History Metrics Supplementary material Data/Code Preview PDF 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. Competing Interest Statement PF, DD and FP filed a patent regarding TDP-43 related circRNAs. PF is founder, advisor, and holds shares in Trace Neuroscience Inc. MJK performs consulting for and holds shares in Trace Neuroscience Inc. Footnotes https://www.ebi.ac.uk/biostudies/arrayexpress/studies/E-MTAB-15433 https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE137810 https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE124439 https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE116622 https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE153960 https://www.ncbi.nlm.nih.gov/bioproject/PRJNA1256902 Funder Information Declared Target ALS, https://ror.org/03fsqvg68 National Institute of Health , U54NS123743 Packard Center for ALS Research Trace Neuroscience Inc Medical Research Council, https://ror.org/03x94j517 Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license . Back to top Previous Posted September 20, 2026. Download PDF Supplementary Material Data/Code Email Thank you for your interest in spreading the word about bioRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. You are going to email the following TDP-43 dysfunction induces cryptic circular RNAs in ALS/FTD Message Subject (Your Name) has forwarded a page to you from bioRxiv Message Body (Your Name) thought you would like to see this page from the bioRxiv website. Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions. Share TDP-43 dysfunction induces cryptic circular RNAs in ALS/FTD Dario Dattilo , Flaminia Pellegrini , Simone Barattucci , Anna-Leigh Brown , Jose Norberto S. Vargas , Ariana Gatt , Ryan Morrie , Georgiana Miller , Iris Bachmutsky , Zachary McEachin , Mingee Chung , Matthew J. Keuss , Eugeni Ryadnov , Matteo Zanovello , Puja R. Mehta , Francesca Mattedi , Michela Barioglio , Shubha Kamath , Sarah E Kargbo-Hill , Joanna Palade , Isabelle Kowal , Jonathan Glass , Marla Gearing , Edward B Lee , Melissa E Murray , Dennis W Dickson , NYGC ALS Consortium , Eric M Green , Nicholas T Seyfried , Sanjay Chandriani , Michael Ward , Pietro Fratta bioRxiv 2026.09.17.752342; doi: https://doi.org/10.64898/2026.09.17.752342 Share This Article: Copy Citation Tools TDP-43 dysfunction induces cryptic circular RNAs in ALS/FTD Dario Dattilo , Flaminia Pellegrini , Simone Barattucci , Anna-Leigh Brown , Jose Norberto S. Vargas , Ariana Gatt , Ryan Morrie , Georgiana Miller , Iris Bachmutsky , Zachary McEachin , Mingee Chung , Matthew J. Keuss , Eugeni Ryadnov , Matteo Zanovello , Puja R. Mehta , Francesca Mattedi , Michela Barioglio , Shubha Kamath , Sarah E Kargbo-Hill , Joanna Palade , Isabelle Kowal , Jonathan Glass , Marla Gearing , Edward B Lee , Melissa E Murray , Dennis W Dickson , NYGC ALS Consortium , Eric M Green , Nicholas T Seyfried , Sanjay Chandriani , Michael Ward , Pietro Fratta bioRxiv 2026.09.17.752342; doi: https://doi.org/10.64898/2026.09.17.752342 Citation Manager Formats BibTeX Bookends EasyBib EndNote (tagged) EndNote 8 (xml) Medlars Mendeley Papers RefWorks Tagged Ref Manager RIS Zotero Tweet Widget Facebook Like Google Plus One Subject Areas All Articles Animal Behavior and Cognition (8013) Biochemistry (18739) Bioengineering (14888) Bioinformatics (44418) Biophysics (22599) Cancer Biology (19723) Cell Biology (26899) Clinical Trials (138) Developmental Biology (13965) Ecology (21005) Epidemiology (2067) Evolutionary Biology (25455) Genetics (16166) Genomics (23507) Immunology (18705) Microbiology (42503) Molecular Biology (18059) Neuroscience (93451) Paleontology (700) Pathology (2977) Pharmacology and Toxicology (5095) Physiology (8114) Plant Biology (15999) Scientific Communication and Education (2095) Synthetic Biology (4560) Systems Biology (10235) Zoology (2391)
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