{"doi":"10.1016/j.celrep.2021.109399","title":"Neuronal VCP loss of function recapitulates FTLD-TDP pathology","abstract":"The pathogenic mechanism by which dominant mutations in VCP cause multisystem proteinopathy (MSP), a rare neurodegenerative disease that presents as fronto-temporal lobar degeneration with TDP-43 inclusions (FTLD-TDP), remains unclear. To explore this, we inactivate VCP in murine postnatal forebrain neurons (VCP conditional knockout [cKO]). VCP cKO mice have cortical brain atrophy, neuronal loss, autophago-lysosomal dysfunction, and TDP-43 inclusions resembling FTLD-TDP pathology. Conditional expression of a single disease-associated mutation, VCP-R155C, in a VCP null background similarly recapitulates features of VCP inactivation and FTLD-TDP, suggesting that this MSP mutation is hypomorphic. Comparison of transcriptomic and proteomic datasets from genetically defined patients with FTLD-TDP reveal that progranulin deficiency and VCP insufficiency result in similar profiles. These data identify a loss of VCP-dependent functions as a mediator of FTLD-TDP and reveal an unexpected biochemical similarity with progranulin deficiency.","journal":"Cell Reports","year":2021,"id":162245,"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":49,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9623,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":678703,"name":"Jiang Zhu","orcid":"0000-0002-6860-8739","position":1,"is_corresponding":false},{"id":236544,"name":"Jason D. Ulrich","orcid":"0000-0002-4743-926X","position":2,"is_corresponding":false},{"id":266771,"name":"Abdallah M. Eteleeb","orcid":"0000-0001-9045-250X","position":3,"is_corresponding":false},{"id":236538,"name":"Andrew D. Sauerbeck","orcid":"0000-0002-4586-0579","position":4,"is_corresponding":false},{"id":354897,"name":"Sydney J. Reitz","orcid":null,"position":5,"is_corresponding":false},{"id":679461,"name":"Khalid Arhzaouy","orcid":null,"position":6,"is_corresponding":false},{"id":511483,"name":"Chiseko Ikenaga","orcid":"0000-0003-2264-1696","position":7,"is_corresponding":false},{"id":225564,"name":"Carla M. Yuede","orcid":"0000-0001-6362-4767","position":8,"is_corresponding":false},{"id":489547,"name":"Sara K. Pittman","orcid":null,"position":9,"is_corresponding":false},{"id":340062,"name":"Feng Wang","orcid":"0009-0007-5238-8704","position":10,"is_corresponding":false},{"id":655813,"name":"Shan Li","orcid":"0000-0002-2146-2453","position":11,"is_corresponding":false},{"id":230679,"name":"Bruno A. Benítez","orcid":"0000-0002-2699-3878","position":12,"is_corresponding":false},{"id":230680,"name":"Carlos Cruchaga","orcid":"0000-0002-0276-2899","position":13,"is_corresponding":false},{"id":236543,"name":"Terrance T. Kummer","orcid":"0000-0001-8938-8280","position":14,"is_corresponding":false},{"id":27580,"name":"Oscar Harari","orcid":"0000-0002-2635-6975","position":15,"is_corresponding":false},{"id":340064,"name":"Tsui‐Fen Chou","orcid":"0000-0003-2410-2186","position":16,"is_corresponding":false},{"id":651587,"name":"Rolf Schröder","orcid":"0000-0002-2772-2615","position":17,"is_corresponding":false},{"id":678704,"name":"Christoph S. Clemen","orcid":"0000-0002-1291-4219","position":18,"is_corresponding":false},{"id":420105,"name":"Conrad C. Weihl","orcid":"0000-0002-3816-6124","position":19,"is_corresponding":false},{"id":678702,"name":"Abubakar Wani","orcid":"0000-0001-7079-3278","position":0,"is_corresponding":true}],"reference_count":79,"raw_metadata":null,"created_at":"2026-07-18T23:45:00.600065Z","pmid":"34289347","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":[]}