{
  "id": 8781637,
  "title": "TDP-43 dysfunction induces cryptic circular RNAs in ALS/FTD",
  "url": "https://urgent.news/2026/09/20/tdp-43-dysfunction-induces-cryptic-circular-rnas-in-als-ftd",
  "topic": "science",
  "section": "Science",
  "published": "2026-09-20T00:00:00.000Z",
  "source": {
    "name": "bioRxiv",
    "slug": "biorxiv",
    "url": "https://www.biorxiv.org/content/10.64898/2026.09.17.752342v1?rss=1"
  },
  "original_language": "en",
  "account": "Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are characterized by nuclear depletion of TDP-43, which leads to widespread RNA misprocessing, including the formation of cryptic exons. Researchers have now discovered that TDP-43 dysfunction also induces the de novo formation of cryptic circular RNAs (c-circRNAs) in multiple human neuronal cell models. By analyzing post-mortem brain transcriptomic data, they identified specific c-circRNAs linked to ALS and FTD cases with TDP-43 pathology. Their highly sensitive circRNA detection assays enabled them to distinguish TDP-43 pathology in human CNS tissues with a 0.99 AUC. Intriguingly, these c-circRNAs can co-occur with cryptic linear splicing events, revealing complex RNA misprocessing hotspots that result in loss of disease-relevant proteins like RPTOR and EHMT1. One such c-circRNA originates from UNC13A, a gene previously associated with an ALS/FTD genetic risk factor and currently being explored as a therapeutic target using splice-switching antisense oligonucleotides (ASOs). The researchers found that c-circUNC13A is co-regulated with the linear cryptic transcript and that suppressing UNC13A cryptic exon reduces c-circUNC13A levels in cultured neurons and in vivo, making it a promising target engagement biomarker for upcoming UNC13A-directed therapies. This groundbreaking work sheds light on a novel molecular mechanism behind TDP-43 dysfunction, offering new perspectives on disease pathogenesis and the urgent need for improved pathology biomarkers.",
  "summary": "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…",
  "key_points": [],
  "editors_take": null,
  "illustration": null,
  "coverage": {
    "outlets": 2,
    "also_reported_by": [
      {
        "outlet": "bioRxiv",
        "title": "Loss of TDP-43 function drives cryptic circular RNAs in neurodegenerative diseases",
        "url": "https://urgent.news/2026/09/20/loss-of-tdp-43-function-drives-cryptic-circular-rnas-in",
        "published": "2026-09-20T00:00:00.000Z"
      }
    ]
  },
  "ai_generated": true,
  "disclaimer": "Summaries, key points and the editor’s take are written by software from other outlets’ reporting and may contain errors — always check the linked original."
}