{"doi":"10.1101/2025.06.28.661837","title":"Inhibition of nonsense-mediated decay in TDP-43 deficient neurons reveals novel cryptic exons","abstract":"Abstract TAR DNA-binding protein 43 kDa (TDP-43) is an essential splicing repressor whose loss of function underlies the pathophysiology of amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD). Nuclear clearance of TDP-43 disrupts its function and leads to the inclusion of aberrant cryptic exons. These cryptic exons frequently introduce premature termination codons resulting in the degradation of affected transcripts through nonsense-mediated mRNA decay (NMD). Conventional RNA sequencing approaches thus may fail to detect cryptic exons that are efficiently degraded by NMD, precluding identification of potential therapeutic targets. We generated a comprehensive set of neuronal targets of TDP-43 in human iPSC-derived i 3 Neurons (i 3 N) by combining TDP-43 knockdown with inhibition of multiple factors essential for NMD, revealing novel cryptic targets. We then restored expression of selected NMD targets in TDP-43 deficient i 3 Ns and determined which genes improved neuronal viability. Our findings highlight the role of NMD in masking cryptic splicing events and identify novel potential therapeutic targets for TDP-43-related neurodegenerative disorders.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":554782,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9542,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1023923,"name":"Yingzhi Ye","orcid":"0000-0002-7380-6529","position":1,"is_corresponding":false},{"id":872394,"name":"Yini Li","orcid":"0000-0003-2213-0650","position":2,"is_corresponding":false},{"id":1326987,"name":"Parker S. Sandal","orcid":"0009-0006-4452-2400","position":3,"is_corresponding":false},{"id":664919,"name":"Philip C. Wong","orcid":"0000-0001-8162-3274","position":4,"is_corresponding":false},{"id":636616,"name":"Shuying Sun","orcid":"0000-0002-8449-7370","position":5,"is_corresponding":false},{"id":258253,"name":"Jonathan P. Ling","orcid":"0000-0003-1927-9729","position":6,"is_corresponding":false},{"id":763261,"name":"Irika R. Sinha","orcid":"0000-0001-6440-7019","position":0,"is_corresponding":true}],"reference_count":96,"raw_metadata":null,"created_at":"2026-07-19T02:54:54.542303Z","pmid":"40667039","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}