{"doi":"10.1101/2023.06.19.544278","title":"Human iPSC 4R tauopathy model uncovers modifiers of tau propagation","abstract":"SUMMARY Tauopathies are age-associated neurodegenerative diseases whose mechanistic underpinnings remain elusive, partially due to lack of appropriate human models. Current human induced pluripotent stem cell (hiPSC)-derived neurons express very low levels of 4-repeat (4R)-tau isoforms that are normally expressed in adult brain. Here, we engineered new iPSC lines to express 4R-tau and 4R-tau carrying the P301S MAPT mutation when differentiated into neurons. 4R-P301S neurons display progressive Tau inclusions upon seeding with Tau fibrils and recapitulate features of tauopathy phenotypes, including shared transcriptomic signatures, autophagic body accumulation, and impaired neuronal activity. A CRISPRi screen of genes associated with Tau pathobiology identified over 500 genetic modifiers of Tau-seeding-induced Tau propagation, including retromer VPS29 and the UFMylation cascade as top modifiers. In AD brains, the UFMylation cascade is altered in neurofibrillary-tangle-bearing neurons. Inhibiting the UFMylation cascade suppressed seeding-induced Tau propagation. This model provides a powerful platform to identify novel therapeutic strategies for 4R tauopathy.","journal":"学術講演梗概集. C-1, 構造III, 木質構造, 鉄骨構造, 鉄骨鉄筋コンクリート構造","year":2023,"id":391025,"datarank":0.32958368660043297,"base_score":2.1972245773362196,"endowment":2.1972245773362196,"self_citation_contribution":0.32958368660043297,"citation_network_contribution":0.0,"self_endowment_contribution":0.32958368660043297,"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":0.9501,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":21336,"name":"Alice Maria Giani","orcid":"0000-0001-8805-7826","position":1,"is_corresponding":false},{"id":820649,"name":"Jesús Madero‐Pérez","orcid":"0000-0002-3473-6011","position":2,"is_corresponding":false},{"id":109213,"name":"Zeping Zhao","orcid":null,"position":3,"is_corresponding":false},{"id":354608,"name":"Avi J. Samelson","orcid":null,"position":4,"is_corresponding":false},{"id":270692,"name":"Man Ying Wong","orcid":"0000-0002-2165-9328","position":5,"is_corresponding":false},{"id":747750,"name":"Alessandro Evangelisti","orcid":null,"position":6,"is_corresponding":false},{"id":295940,"name":"Li Fan","orcid":"0000-0003-1780-6919","position":7,"is_corresponding":false},{"id":1163299,"name":"Tatyana Pozner","orcid":"0000-0002-0723-9319","position":8,"is_corresponding":false},{"id":821041,"name":"Maria Mercédes","orcid":null,"position":9,"is_corresponding":false},{"id":1015560,"name":"Pearly Ye","orcid":null,"position":10,"is_corresponding":false},{"id":1163794,"name":"Tark Patel","orcid":null,"position":11,"is_corresponding":false},{"id":1014658,"name":"Allan Yarahmady","orcid":"0009-0008-0397-7294","position":12,"is_corresponding":false},{"id":1014655,"name":"Gillian Carling","orcid":"0000-0002-1504-1716","position":13,"is_corresponding":false},{"id":27604,"name":"Virginia M.‐Y. Lee","orcid":"0000-0003-3536-6902","position":14,"is_corresponding":false},{"id":814166,"name":"Manu Sharma","orcid":"0000-0001-7394-2419","position":15,"is_corresponding":false},{"id":275684,"name":"Sue‐Ann Mok","orcid":"0000-0003-4593-3368","position":16,"is_corresponding":false},{"id":270700,"name":"Wenjie Luo","orcid":"0000-0003-3752-8266","position":17,"is_corresponding":false},{"id":445309,"name":"Mingrui Zhao","orcid":"0009-0006-3882-8526","position":18,"is_corresponding":false},{"id":218683,"name":"Martin Kampmann","orcid":"0000-0002-3819-7019","position":19,"is_corresponding":false},{"id":236876,"name":"Shiaoching Gong","orcid":"0000-0002-5907-5539","position":20,"is_corresponding":false},{"id":250399,"name":"Li Gan","orcid":"0000-0003-4600-275X","position":21,"is_corresponding":false},{"id":1159755,"name":"C Bravo","orcid":"0000-0001-9781-8922","position":0,"is_corresponding":true}],"reference_count":82,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:18:42.653719Z","pmid":"37745431","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":[]}