{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "UCL Queen Square Motor Neuron Disease Centre, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, UCL, London, UK; The Francis Crick"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 32,
  "authors": [
    {
      "name": "D. Dattilo"
    },
    {
      "name": "F. Pellegrini"
    },
    {
      "name": "S. Barattucci"
    },
    {
      "name": "A.-L. Brown"
    },
    {
      "name": "J. N. S. Vargas"
    },
    {
      "name": "A. Gatt"
    },
    {
      "name": "R. Morrie"
    },
    {
      "name": "G. Miller"
    },
    {
      "name": "I. Bachmutsky"
    },
    {
      "name": "Z. McEachin"
    },
    {
      "name": "M. Chung"
    },
    {
      "name": "M. J. Keuss"
    },
    {
      "name": "E. Ryadnov"
    },
    {
      "name": "M. Zanovello"
    },
    {
      "name": "P. R. Mehta"
    },
    {
      "name": "F. Mattedi"
    },
    {
      "name": "M. Barioglio"
    },
    {
      "name": "S. Kamath"
    },
    {
      "name": "S. E. Kargbo-Hill"
    },
    {
      "name": "J. Palade"
    },
    {
      "name": "I. Kowal"
    },
    {
      "name": "J. Glass"
    },
    {
      "name": "M. Gearing"
    },
    {
      "name": "E. B. Lee"
    },
    {
      "name": "M. E. Murray"
    },
    {
      "name": "D. W. Dickson"
    },
    {
      "name": "NYGC ALS Consortium"
    },
    {
      "name": "E. M. Green"
    },
    {
      "name": "N. T. Seyfried"
    },
    {
      "name": "S. Chandriani"
    },
    {
      "name": "M. Ward"
    },
    {
      "affs": [
        0
      ],
      "name": "P. Fratta"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/dhfk8p6yan4hj.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.17.752342",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.09.17.752342v1.full",
  "id": "dhfk8p6yan4hj",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.09.17.752342v1",
  "language": null,
  "licence": "CC-BY-NC",
  "licence_label": "CC BY-NC",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "neuroscience"
    ],
    [
      "openalex",
      "2728|Amyotrophic Lateral Sclerosis Research"
    ]
  ],
  "openalex": "W7213780656",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.09.17.752342v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-17",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/dhfk8p6yan4hj.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:23:24Z",
      "native_id": "10.64898/2026.09.17.752342",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.09.17.752342v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:neuroscience",
      "subfield": "neuroscience"
    }
  ],
  "title": "TDP-43 dysfunction induces cryptic circular RNAs in ALS/FTD",
  "title_text": "TDP-43 dysfunction induces cryptic circular RNAs in ALS/FTD",
  "type": "preprint",
  "updated_at": "2026-10-30T12:23:24Z",
  "url": "https://research.draconitic.com/paper/dhfk8p6yan4hj",
  "venue": "bioRxiv",
  "versions": []
}