{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T04:46:05Z","timestamp":1791521165615,"version":"4.3.4"},"posted":{"date-parts":[[2025,11,23]]},"group-title":"Molecular Biology","reference-count":77,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,11,23]],"date-time":"2025-11-23T00:00:00Z","timestamp":1763856000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,11,23]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Cryptic splicing caused by TDP-43 proteinopathy is a hallmark of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, which cryptic splicing events (CEs) are the most sensitive to TDP-43 depletion, where CEs localise within cells, and how specific CEs are in human tissues is poorly defined. Analyses of\n                  <jats:italic>in vitro<\/jats:italic>\n                  TDP-43 knockdowns and postmortem RNA-seq datasets revealed that a small subset out of thousands of CEs are specific markers for TDP-43 proteinopathy\n                  <jats:italic>in vivo<\/jats:italic>\n                  . Nonsense-mediated decay (NMD) masked a portion of CEs, influencing their subcellular localization and detectability in tissue. Dose-dependent TDP-43 depletion identified \u201cearly-responsive\u201d CEs, which possess stronger splice sites and denser, more canonical TDP-43 binding motifs. Finally, we developed a composite cryptic burden score that effectively captured TDP-43 pathology across heterogeneous tissues and correlated with regional vulnerability and genetic background. Our work identifies robust biomarkers and offers new insights into TDP-43-mediated splicing dysregulation in neurodegeneration.\n                <\/jats:p>","DOI":"10.1101\/2025.11.23.689722","type":"posted-content","created":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T03:35:14Z","timestamp":1763955314000},"source":"Crossref","is-referenced-by-count":6,"title":["Sensitivity to TDP-43 loss and degradation resistance determine cryptic exon biomarker potential"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1493-208X","authenticated-orcid":false,"given":"Anna-Leigh","family":"Brown","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3343-1547","authenticated-orcid":false,"given":"Matteo","family":"Zanovello","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3400-9719","authenticated-orcid":false,"given":"Alla","family":"Mikheenko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2774-3835","authenticated-orcid":false,"given":"Dario","family":"Dattilo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5874-5334","authenticated-orcid":false,"given":"Flaminia","family":"Pellegrini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2087-5050","authenticated-orcid":false,"given":"Sam","family":"Bryce-Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0306-5796","authenticated-orcid":false,"given":"Francesca","family":"Mattedi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0255-407X","authenticated-orcid":false,"given":"Puja R.","family":"Mehta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5529-0883","authenticated-orcid":false,"given":"Jose Norberto S.","family":"Vargas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"NYGC ALS Consortium","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6274-6620","authenticated-orcid":false,"given":"Jack","family":"Humphrey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2628-4115","authenticated-orcid":false,"given":"Matthew J.","family":"Keuss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8762-8188","authenticated-orcid":false,"given":"Pietro","family":"Fratta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025112509151109000_2025.11.23.689722v1.1","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/20.7.1774"},{"key":"2025112509151109000_2025.11.23.689722v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/nn.2778"},{"key":"2025112509151109000_2025.11.23.689722v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2006.10.093"},{"key":"2025112509151109000_2025.11.23.689722v1.4","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-008-0480-1"},{"key":"2025112509151109000_2025.11.23.689722v1.5","doi-asserted-by":"publisher","DOI":"10.1126\/science.1134108"},{"key":"2025112509151109000_2025.11.23.689722v1.6","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp-2020-322983"},{"key":"2025112509151109000_2025.11.23.689722v1.7","doi-asserted-by":"publisher","DOI":"10.1126\/science.aab0983"},{"key":"2025112509151109000_2025.11.23.689722v1.8","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-04436-3"},{"key":"2025112509151109000_2025.11.23.689722v1.9","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-04424-7"},{"key":"2025112509151109000_2025.11.23.689722v1.10","doi-asserted-by":"publisher","DOI":"10.1101\/2025.06.28.661837"},{"key":"2025112509151109000_2025.11.23.689722v1.11","doi-asserted-by":"publisher","DOI":"10.1101\/2025.07.09.664014"},{"key":"2025112509151109000_2025.11.23.689722v1.12","doi-asserted-by":"crossref","unstructured":"Humphrey, J. , Emmett, W. , Fratta, P. , Isaacs, A. 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