{"doi":"10.1101/2024.03.27.587011","title":"Large-scale RNA-seq mining reveals ciclopirox triggers TDP-43 cryptic exons","abstract":"Nuclear clearance and cytoplasmic aggregation of TDP-43 in neurons, initially identified in ALS-FTD, are hallmark pathological features observed across a spectrum of neurodegenerative diseases. We previously found that TDP-43 loss-of-function leads to the transcriptome-wide inclusion of deleterious cryptic exons in brains and biofluids post-mortem as well as during the presymptomatic stage of ALS-FTD, but upstream mechanisms that lead to TDP-43 dysregulation remain unclear. Here, we developed a web-based resource (SnapMine) to determine the levels of TDP-43 cryptic exon inclusion across hundreds of thousands of publicly available RNA sequencing datasets. We established cryptic exon inclusion across a variety of human cells and tissues to provide ground truth references for future studies on TDP-43 dysregulation. We then explored studies that were entirely unrelated to TDP-43 or neurodegeneration and found that ciclopirox olamine (CPX), an FDA-approved antifungal, can trigger the inclusion of TDP-43-associated cryptic exons in a variety of mouse and human primary cells. CPX induction of cryptic exon occurs via heavy metal toxicity and oxidative stress, suggesting that similar vulnerabilities could play a role in neurodegeneration. Our work demonstrates how diverse datasets can be linked through common biological features and underscores that public archives of sequencing data represent a vastly underutilized resource with tremendous potential for uncovering novel insights into complex biological mechanisms and diseases.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":484848,"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":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9495,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1326987,"name":"Parker S. Sandal","orcid":"0009-0006-4452-2400","position":1,"is_corresponding":false},{"id":1326988,"name":"G Burns","orcid":"0000-0001-8691-779X","position":2,"is_corresponding":false},{"id":1326989,"name":"Aswathy Peethambaran Mallika","orcid":"0000-0003-0303-5156","position":3,"is_corresponding":false},{"id":728782,"name":"Katherine E. Irwin","orcid":"0000-0001-8941-4557","position":4,"is_corresponding":false},{"id":339446,"name":"Anna Lourdes Cruz","orcid":"0000-0002-9889-3868","position":5,"is_corresponding":false},{"id":1205440,"name":"Vania Wang","orcid":"0000-0002-9428-7019","position":6,"is_corresponding":false},{"id":919515,"name":"Josué Llamas Rodríguez","orcid":"0000-0002-5532-7786","position":7,"is_corresponding":false},{"id":664919,"name":"Philip C. Wong","orcid":"0000-0001-8162-3274","position":8,"is_corresponding":false},{"id":258253,"name":"Jonathan P. Ling","orcid":"0000-0003-1927-9729","position":9,"is_corresponding":false},{"id":763261,"name":"Irika R. Sinha","orcid":"0000-0001-6440-7019","position":0,"is_corresponding":true}],"reference_count":98,"raw_metadata":null,"created_at":"2026-07-19T02:07:42.971417Z","pmid":"38585725","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":[]}