{"doi":"10.21203/rs.3.rs-3036166/v1","title":"High-Content Small Molecule Screen Identifies a Novel Compound That Restores AP-4-Dependent Protein Trafficking in Neuronal Models of AP-4-Associated Hereditary Spastic Paraplegia","abstract":"Abstract Unbiased phenotypic screens in patient-relevant disease models offer the potential to detect novel therapeutic targets for rare diseases. In this study, we developed a high-throughput screening assay to identify molecules that correct aberrant protein trafficking in adaptor protein complex 4 (AP-4) deficiency, a rare but prototypical form of childhood-onset hereditary spastic paraplegia, characterized by mislocalization of the autophagy protein ATG9A. Using high-content microscopy and an automated image analysis pipeline, we screened a diversity library of 28,864 small molecules and identified a lead compound, C-01 , that restored ATG9A pathology in multiple disease models, including patient-derived fibroblasts and induced pluripotent stem cell-derived neurons. We used multiparametric orthogonal strategies and integrated transcriptomic and proteomic approaches to delineate putative molecular targets of C-01 and potential mechanisms of action. Our results define molecular regulators of intracellular ATG9A trafficking and characterize a lead compound for the treatment of AP-4 deficiency, providing important proof-of-concept data for future Investigational New Drug (IND)-enabling studies.","journal":"Research Square","year":2023,"id":399792,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9432,"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":584740,"name":"Barbara Brechmann","orcid":"0000-0003-1228-4349","position":1,"is_corresponding":false},{"id":1176181,"name":"Cedric Boeger","orcid":null,"position":2,"is_corresponding":false},{"id":480435,"name":"Wardiya Afshar Saber","orcid":"0000-0001-9488-7893","position":3,"is_corresponding":false},{"id":771405,"name":"Hellen Jumo","orcid":"0000-0003-0495-5317","position":4,"is_corresponding":false},{"id":1081833,"name":"Dosh Whye","orcid":"0000-0002-6895-9627","position":5,"is_corresponding":false},{"id":1082273,"name":"Delaney Wood","orcid":null,"position":6,"is_corresponding":false},{"id":17321,"name":"Lara Wahlster","orcid":"0000-0001-8409-7580","position":7,"is_corresponding":false},{"id":767002,"name":"Julian E. Alecu","orcid":"0000-0002-1420-9775","position":8,"is_corresponding":false},{"id":771407,"name":"M. L. ZIEGLER","orcid":"0000-0002-0504-7815","position":9,"is_corresponding":false},{"id":1175834,"name":"Marlene Scheffold","orcid":"0000-0002-6443-5594","position":10,"is_corresponding":false},{"id":497313,"name":"Kellen D. Winden","orcid":"0000-0001-5816-3724","position":11,"is_corresponding":false},{"id":1065742,"name":"Jed L. Hubbs","orcid":"0000-0002-3923-3392","position":12,"is_corresponding":false},{"id":544034,"name":"Elizabeth D. Buttermore","orcid":"0000-0003-3194-5413","position":13,"is_corresponding":false},{"id":498348,"name":"Lee Barrett","orcid":null,"position":14,"is_corresponding":false},{"id":324079,"name":"Georg H. H. Borner","orcid":"0000-0002-3166-3435","position":15,"is_corresponding":false},{"id":861934,"name":"Alexandra K. Davies","orcid":"0000-0002-1594-8780","position":16,"is_corresponding":false},{"id":40872,"name":"Mustafa Sahin","orcid":"0000-0001-7044-2953","position":17,"is_corresponding":false},{"id":584752,"name":"Darius Ebrahimi‐Fakhari","orcid":"0000-0002-0026-4714","position":18,"is_corresponding":false},{"id":879690,"name":"Afshin Saffari","orcid":"0000-0003-4119-7519","position":0,"is_corresponding":true}],"reference_count":88,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:19:56.084411Z","pmid":"37398196","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":[]}