{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:20:01Z","timestamp":1792790401264,"version":"4.5.0"},"posted":{"date-parts":[[2026,9,20]]},"group-title":"Neuroscience","reference-count":69,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T00:00:00Z","timestamp":1789862400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"id":[{"id":"https:\/\/ror.org\/03fsqvg68","id-type":"ROR","asserted-by":"publisher"}]},{"name":"National Institute of Health","award":["U54NS123743"],"award-info":[{"award-number":["U54NS123743"]}]},{"name":"Packard Center for ALS Research","id":[{"id":"https:\/\/ror.org\/042fhmq33","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Trace Neuroscience Inc"},{"id":[{"id":"https:\/\/ror.org\/03x94j517","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,20]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  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\n                  <jats:italic>RPTOR<\/jats:italic>\n                  and\n                  <jats:italic>EHMT1<\/jats:italic>\n                  . Notably, one of these c-circRNAs originates from\n                  <jats:italic>UNC13A<\/jats:italic>\n                  , 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.\n                <\/jats:p>","DOI":"10.64898\/2026.09.17.752342","type":"posted-content","created":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T23:20:11Z","timestamp":1789946411000},"source":"Crossref","is-referenced-by-count":0,"title":["TDP-43 dysfunction induces cryptic circular RNAs in ALS\/FTD"],"prefix":"10.64898","author":[{"given":"Dario","family":"Dattilo","sequence":"first","affiliation":[{"name":"UCL Queen Square Motor Neuron Disease Centre, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, UCL, London, UK"},{"name":"The Francis Crick Institute, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Flaminia","family":"Pellegrini","sequence":"additional","affiliation":[{"name":"UCL Queen Square Motor Neuron Disease Centre, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, UCL, London, UK"},{"name":"The Francis Crick Institute, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Barattucci","sequence":"additional","affiliation":[{"name":"UCL Queen Square Motor Neuron Disease Centre, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, UCL, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna-Leigh","family":"Brown","sequence":"additional","affiliation":[{"name":"UCL Queen Square Motor Neuron Disease Centre, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, UCL, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose Norberto S.","family":"Vargas","sequence":"additional","affiliation":[{"name":"UCL Queen Square Motor Neuron Disease Centre, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, UCL, London, 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