{"doi":"10.1101/2025.09.29.679403","title":"Integrative multiomic analysis links TDP-43-driven splicing defects to cascading proteomic disruption of ALS/FTD pathways","abstract":"Loss of nuclear TDP-43 is a hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although TDP-43 is known to regulate RNA processing, including repression of cryptic exons, we currently lack a systems-level understanding of the consequences of TDP-43 loss. To address this, we generated multiomic datasets, including RNA-seq and proteomics, from human iPSC-derived neurons depleted of TDP-43. We found that differentially spliced genes, many expressing cryptic exons, had the greatest protein reductions. Surprisingly, nearly half of differentially expressed proteins were neither mis-spliced, nor differentially expressed genes; most of these also had no reported mis-splicing in seven additional post-mortem and iPSC-derived neuron datasets. Integrative network analysis identified a high-confidence disease-specific subnetwork of over 700 interacting proteins, enriched for mRNA processing, synaptic function, and autophagy. Comparison with post-mortem ALS and FTD samples revealed convergent protein and pathway disruptions. We experimentally validated network-predicted effects of cryptic splicing in ATG4B, STMN2, and DAPK1. Our analyses reveal new TDP-43-dependent molecular cascades and nominate central genes as potential ALS/FTD therapeutic targets.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":556798,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.5628,"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":1456901,"name":"Zhengde Liu","orcid":null,"position":1,"is_corresponding":false},{"id":1431505,"name":"Keyana Blake","orcid":"0009-0006-2566-5692","position":2,"is_corresponding":false},{"id":567365,"name":"Yue Qi","orcid":"0000-0003-1914-8710","position":3,"is_corresponding":false},{"id":1456902,"name":"Sasha Rollinson","orcid":null,"position":4,"is_corresponding":false},{"id":839264,"name":"Sahba Seddighi","orcid":"0000-0003-1920-2828","position":5,"is_corresponding":false},{"id":1456903,"name":"Mohammad Alsaidi","orcid":null,"position":6,"is_corresponding":false},{"id":863755,"name":"Stanislav Tsitkov","orcid":null,"position":7,"is_corresponding":false},{"id":238155,"name":"Mercedes Prudencio","orcid":"0000-0002-4894-4858","position":8,"is_corresponding":false},{"id":228616,"name":"Leonard Petrucelli","orcid":"0000-0003-2959-129X","position":9,"is_corresponding":false},{"id":54753,"name":"Dennis W. Dickson","orcid":"0000-0001-7189-7917","position":10,"is_corresponding":false},{"id":238158,"name":"Anna‐Leigh Brown","orcid":"0000-0003-1493-208X","position":11,"is_corresponding":false},{"id":668989,"name":"Pietro Fratta","orcid":"0000-0002-7554-1632","position":12,"is_corresponding":false},{"id":283900,"name":"Hong Joo Kim","orcid":"0000-0002-9157-1612","position":13,"is_corresponding":false},{"id":228281,"name":"J. Paul Taylor","orcid":"0000-0002-5794-0349","position":14,"is_corresponding":false},{"id":225567,"name":"Michael E. Ward","orcid":"0000-0002-5296-8051","position":15,"is_corresponding":false},{"id":23597,"name":"Ernest Fraenkel","orcid":"0000-0001-9249-8181","position":16,"is_corresponding":false},{"id":238159,"name":"Sarah E. Hill","orcid":"0000-0002-8499-7455","position":17,"is_corresponding":false},{"id":68568,"name":"Velina Kozareva","orcid":"0000-0001-7192-8672","position":0,"is_corresponding":true}],"reference_count":86,"raw_metadata":null,"created_at":"2026-07-19T02:55:13.130091Z","pmid":"41256508","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":[]}