{"doi":"10.1007/s13311-022-01199-7","title":"A Brain-Penetrant Stearoyl-CoA Desaturase Inhibitor Reverses α-Synuclein Toxicity","abstract":"Increasing evidence has shown that Parkinson's disease (PD) impairs midbrain dopaminergic, cortical and other neuronal subtypes in large part due to the build-up of lipid- and vesicle-rich α-synuclein (αSyn) cytotoxic inclusions. We previously identified stearoyl-CoA desaturase (SCD) as a potential therapeutic target for synucleinopathies. A brain-penetrant SCD inhibitor, YTX-7739, was developed and has entered Phase 1 clinical trials. Here, we report the efficacy of YTX-7739 in reversing pathological αSyn phenotypes in various in vitro and in vivo PD models. In cell-based assays, YTX-7739 decreased αSyn-mediated neuronal death, reversed the abnormal membrane interaction of amplified E46K (\"3K\") αSyn, and prevented pathological phenotypes in A53T and αSyn triplication patient-derived neurospheres, including dysregulated fatty acid profiles and pS129 αSyn accumulation. In 3K PD-like mice, YTX-7739 crossed the blood-brain barrier, decreased unsaturated fatty acids, and prevented progressive motor deficits. Both YTX-7739 treatment and decreasing SCD activity through deletion of one copy of the SCD1 gene (SKO) restored the physiological αSyn tetramer-to-monomer ratio, dopaminergic integrity, and neuronal survival in 3K αSyn mice. YTX-7739 efficiently reduced pS129 + and PK-resistant αSyn in both human wild-type αSyn and 3K mutant mice similar to the level of 3K-SKO. Together, these data provide further validation of SCD as a PD therapeutic target and YTX-7739 as a clinical candidate for treating human α-synucleinopathies.","journal":"Neurotherapeutics","year":2022,"id":251102,"datarank":0.4887144807032224,"base_score":3.258096538021482,"endowment":3.258096538021482,"self_citation_contribution":0.4887144807032224,"citation_network_contribution":0.0,"self_endowment_contribution":0.4887144807032224,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":25,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9628,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":893911,"name":"Chee Yeun Chung","orcid":"0000-0002-5515-650X","position":1,"is_corresponding":false},{"id":893912,"name":"Daniel F. Tardiff","orcid":"0000-0002-5237-9652","position":2,"is_corresponding":false},{"id":893913,"name":"Pascal A. Bechade","orcid":"0000-0003-3705-7791","position":3,"is_corresponding":false},{"id":893914,"name":"Thomas D. McCaffery","orcid":"0000-0002-7633-6008","position":4,"is_corresponding":false},{"id":893915,"name":"Kazuma Shimanaka","orcid":"0000-0001-9786-3571","position":5,"is_corresponding":false},{"id":893916,"name":"Jeonghoon Choi","orcid":"0000-0003-1131-4745","position":6,"is_corresponding":false},{"id":894500,"name":"Belle Chang","orcid":null,"position":7,"is_corresponding":false},{"id":893917,"name":"Waseem Raja","orcid":"0009-0009-9745-970X","position":8,"is_corresponding":false},{"id":894501,"name":"Esther Neves","orcid":null,"position":9,"is_corresponding":false},{"id":894502,"name":"Christopher Burke","orcid":null,"position":10,"is_corresponding":false},{"id":830229,"name":"Xin Jiang","orcid":"0000-0002-7288-8278","position":11,"is_corresponding":false},{"id":376473,"name":"Ping Xu","orcid":"0000-0002-4118-2598","position":12,"is_corresponding":false},{"id":893918,"name":"Vikram Khurana","orcid":"0000-0002-4018-5527","position":13,"is_corresponding":false},{"id":240635,"name":"Ulf Dettmer","orcid":"0000-0001-6676-0107","position":14,"is_corresponding":false},{"id":240634,"name":"Saranna Fanning","orcid":"0000-0003-4638-1331","position":15,"is_corresponding":false},{"id":894503,"name":"Kenneth J. Rhodes","orcid":null,"position":16,"is_corresponding":false},{"id":7839,"name":"Dennis J. Selkoe","orcid":"0000-0001-8846-9767","position":17,"is_corresponding":false},{"id":893919,"name":"Robert H. Scannevin","orcid":"0000-0002-5749-2785","position":18,"is_corresponding":false},{"id":313421,"name":"Silke Nuber","orcid":"0000-0002-2124-6865","position":0,"is_corresponding":true}],"reference_count":68,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:24:37.429628Z","pmid":"35445353","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":[]}