{"doi":"10.1186/s12967-024-05551-7","title":"Tilorone mitigates the propagation of α-synucleinopathy in a midbrain-like organoid model","abstract":"BACKGROUND: Parkinson's disease (PD) is a neurodegenerative condition characterized by the loss of dopaminergic neurons and the accumulation of Lewy-body protein aggregates containing misfolded α-synuclein (α-syn) in a phosphorylated form. The lack of effective models for drug screens has hindered drug development studies for PD. However, the recent development of in vitro brain-like organoids provides a new opportunity for evaluating therapeutic agents to slow the progression of this chronic disease. METHODS: In this study, we used a 3D brain-like organoid model to investigate the potential of repurposing Tilorone, an anti-viral drug, for impeding the propagation of α-synucleinopathy. We assessed the effect of Tilorone on the uptake of fluorescently labeled α-syn preformed fibrils (sPFF) and sPFF-induced apoptosis using confocal microscopy. We also examined Tilorone's impact on the phosphorylation of endogenous α-syn induced by pathogenic sPFF by immunoblotting midbrain-like organoid extracts. Additionally, quantitative RT-PCR and proteomic profiling of sPFF-treated organoids were conducted to evaluate the global impact of Tilorone treatment on tissue homeostasis in the 3D organoid model. RESULTS: Tilorone inhibits the uptake of sPFF in both mouse primary neurons and human midbrain-like organoids. Tilorone also reduces the phosphorylation of endogenous α-syn induced by pathogenic α-syn fibrils and mitigates α-syn fibril-induced apoptosis in midbrain-like organoids. Proteomic profiling of fibril-treated organoids reveals substantial alterations in lipid homeostasis by α-syn fibrils, which are reversed by Tilorone treatment. Given its safety profile in clinics, Tilorone may be further developed as a therapeutic intervention to alleviate the propagation of synucleinopathy in PD patients.","journal":"Journal of Translational Medicine","year":2024,"id":443166,"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":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9633,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1257311,"name":"Meng Liu","orcid":"0000-0003-3114-9003","position":1,"is_corresponding":false},{"id":1257312,"name":"Yue Xu","orcid":"0000-0002-5160-6251","position":2,"is_corresponding":false},{"id":239786,"name":"Juhyung Lee","orcid":"0000-0002-3638-1496","position":3,"is_corresponding":false},{"id":827118,"name":"B. Malique Jones","orcid":"0000-0002-6614-9962","position":4,"is_corresponding":false},{"id":1257313,"name":"Bing Li","orcid":"0000-0001-6909-4752","position":5,"is_corresponding":false},{"id":580298,"name":"Wenwei Huang","orcid":"0000-0002-7756-6577","position":6,"is_corresponding":false},{"id":239793,"name":"Yihong Ye","orcid":"0000-0002-9512-7922","position":7,"is_corresponding":false},{"id":227992,"name":"Wei Zheng","orcid":"0000-0003-1034-0757","position":8,"is_corresponding":false},{"id":239783,"name":"Qi Zhang","orcid":"0000-0002-2639-9158","position":0,"is_corresponding":true}],"reference_count":60,"raw_metadata":null,"created_at":"2026-07-19T02:01:24.471942Z","pmid":"39223664","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":[]}