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While loss of TDP-43 induces aberrant splicing in linear transcripts, its impact on circular RNA (circRNA) biogenesis remains unexplored. Here, we show that TDP-43 depletion in human neurons induces widespread circRNA changes, especially upregulation of a distinct class of cryptic circRNAs that arise specifically upon loss of TDP-43. Some of these cryptic circRNAs incorporate cryptic exons derived from intronic sequences. Notably, these cryptic circRNAs exhibit greater stability than their corresponding linear RNA isoforms and accumulate progressively in neurons. Moreover, cryptic circRNAs are elevated in postmortem brain tissues from ALS, FTD and Alzheimer\u2019s disease (AD) patients. These findings reveal a previously unrecognized role for TDP-43 in repressing cryptic circRNA formation and establish these circRNAs as stable molecular signatures of TDP-43 dysfunction.<\/jats:p>","DOI":"10.64898\/2026.09.17.752169","type":"posted-content","created":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T23:15:11Z","timestamp":1789946111000},"source":"Crossref","is-referenced-by-count":0,"title":["Loss of TDP-43 function drives cryptic circular RNAs in neurodegenerative diseases"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8499-2216","authenticated-orcid":false,"given":"Chengzhang","family":"Zhu","sequence":"first","affiliation":[{"name":"Department of Department of Physiology, Pharmacology & Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"},{"name":"Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"},{"name":"Cellular and Molecular Medicine Graduate Program, Johns 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