{"doi":"10.7554/elife.104057.2","title":"Maintenance of neuronal TDP-43 expression requires axonal lysosome transport","abstract":"Abstract TDP-43 mislocalization and pathology occurs across a range of neurodegenerative diseases, but the pathways that modulate TDP-43 in neurons are not well understood. We generated a Halo-TDP-43 knock-in iPSC line and performed a genome-wide CRISPR interference FACS-based screen to identify modifiers of TDP-43 levels in neurons. A meta-analysis of our screen and publicly available screens identified both specific hits and pathways present across multiple screens, the latter likely responsible for generic protein level maintenance. We identified BORC, a complex required for anterograde lysosome transport, as a specific modifier of TDP-43 protein, but not mRNA, levels in neurons. BORC loss led to longer half-life of TDP-43 and other proteins, suggesting lysosome location is required for proper protein turnover. As such, lysosome location and function are crucial for maintaining TDP-43 protein levels in neurons.","journal":"eLife","year":2025,"id":556658,"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":0.9575,"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":1164743,"name":"Sydney Lawton","orcid":null,"position":1,"is_corresponding":false},{"id":839265,"name":"Joel F. Reyes","orcid":"0000-0002-2354-4874","position":2,"is_corresponding":false},{"id":628682,"name":"James Hawrot","orcid":"0000-0001-8050-8274","position":3,"is_corresponding":false},{"id":472823,"name":"Ashley M. Frankenfield","orcid":"0000-0001-9311-4194","position":4,"is_corresponding":false},{"id":839264,"name":"Sahba Seddighi","orcid":"0000-0003-1920-2828","position":5,"is_corresponding":false},{"id":635173,"name":"Daniel M. Ramos","orcid":"0000-0002-4041-5273","position":6,"is_corresponding":false},{"id":1253732,"name":"Jacob Epstein","orcid":"0009-0003-7979-3532","position":7,"is_corresponding":false},{"id":271541,"name":"Faraz Faghri","orcid":"0000-0001-5744-8728","position":8,"is_corresponding":false},{"id":711589,"name":"Nicholas L. Johnson","orcid":"0009-0004-1464-5050","position":9,"is_corresponding":false},{"id":288883,"name":"Jizhong Zou","orcid":"0000-0003-1021-0549","position":10,"is_corresponding":false},{"id":218683,"name":"Martin Kampmann","orcid":"0000-0002-3819-7019","position":11,"is_corresponding":false},{"id":273092,"name":"John Replogle","orcid":null,"position":12,"is_corresponding":false},{"id":567365,"name":"Yue Qi","orcid":"0000-0003-1914-8710","position":13,"is_corresponding":false},{"id":846356,"name":"Hebao Yuan","orcid":"0000-0003-4425-3678","position":14,"is_corresponding":false},{"id":477558,"name":"Kory R. Johnson","orcid":"0000-0002-6693-3378","position":15,"is_corresponding":false},{"id":1424610,"name":"Dragan Marić","orcid":null,"position":16,"is_corresponding":false},{"id":472825,"name":"Ling Hao","orcid":"0000-0002-0106-5266","position":17,"is_corresponding":false},{"id":130825,"name":"Mike A. Nalls","orcid":null,"position":18,"is_corresponding":false},{"id":225567,"name":"Michael E. Ward","orcid":"0000-0002-5296-8051","position":19,"is_corresponding":false},{"id":303968,"name":"Veronica H. Ryan","orcid":"0000-0001-5121-4672","position":0,"is_corresponding":true}],"reference_count":65,"raw_metadata":null,"created_at":"2026-07-19T02:55:13.130091Z","pmid":null,"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":[]}