{"doi":"10.1101/2025.04.07.646890","title":"Context-dependent Interactors Regulate TDP-43 Dysfunction in ALS/FTLD","abstract":"TDP-43 mislocalization, aggregation, and loss of splicing function are neuropathological hallmarks in over 97% of Amyotrophic Lateral Sclerosis (ALS), 45% of Frontotemporal Lobar Degeneration (FTLD), and 60% of Alzheimer's Disease, which has been reclassified as LATE-NC. However, the mechanisms underlying TDP-43 dysfunction remain elusive. Here, we utilize APEX2-driven proximity labeling and mass spectrometry to characterize the context-dependent TDP-43 interactome in conditions of cytoplasmic mislocalization, impaired RNA-binding contributing to aggregation, and oxidative stress. We describe context-dependent interactors, including disrupted interactions with splicing-related proteins and altered biomolecular condensate (BMC) associations. By integrating ALS and FTLD snRNA-seq data, we uncover disease-relevant molecular alterations and validate our dataset through a functional screen that identifies key TDP-43 regulators. We demonstrate that disrupting nuclear speckle integrity, particularly through the downregulation of the splicing factor SRRM2, promotes TDP-43 mislocalization and loss of function. Additionally, we identify NUFIP2 as an interactor associated with mislocalization that sequesters TDP-43 into cytoplasmic aggregates and co-localizes with TDP-43 pathology in patient tissue. We also highlight HNRNPC as a potent TDP-43 splicing regulator, where precise modulation of TDP-43 or HNRNPC can rescue cryptic exon splicing. These findings provide mechanistic insights and potential therapeutic targets for TDP-43 dysfunction.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":554763,"datarank":0.3567656752194112,"base_score":2.1972245773362196,"endowment":2.1972245773362196,"self_citation_contribution":0.32958368660043297,"citation_network_contribution":0.027181988618978265,"self_endowment_contribution":0.32958368660043297,"citer_contribution":0.027181988618978265,"corpus_percentile":null,"corpus_rank":null,"citation_count":8,"citer_count":8,"citers_with_citation_signal":3,"citers_with_endowment":3,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9545,"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":3019,"name":"Yuehua Zhu","orcid":"0000-0002-9751-7051","position":1,"is_corresponding":false},{"id":1037457,"name":"Bryan Hurtle","orcid":null,"position":2,"is_corresponding":false},{"id":1326074,"name":"Matthew Wright","orcid":"0000-0002-6787-8104","position":3,"is_corresponding":false},{"id":227427,"name":"John Robinson","orcid":"0000-0001-6858-2367","position":4,"is_corresponding":false},{"id":820169,"name":"Jocelyn C. 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Gleixner","orcid":"0000-0001-8241-8408","position":11,"is_corresponding":false},{"id":348906,"name":"Gabriela Grigorean","orcid":"0000-0001-5693-0846","position":12,"is_corresponding":false},{"id":866900,"name":"Feilin Liu","orcid":null,"position":13,"is_corresponding":false},{"id":301313,"name":"Wilfried Rossoll","orcid":"0000-0002-9622-541X","position":14,"is_corresponding":false},{"id":107087,"name":"Edward B. Lee","orcid":"0000-0002-4589-1180","position":15,"is_corresponding":false},{"id":262674,"name":"Evangelos Kiskinis","orcid":"0000-0001-8342-8616","position":16,"is_corresponding":false},{"id":3026,"name":"Maria Chikina","orcid":"0000-0003-2550-5403","position":17,"is_corresponding":false},{"id":501165,"name":"Christopher J. 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