ArticleNature communications2024
High-content screening identifies a small molecule that restores AP-4-dependent protein trafficking in neuronal models of AP-4-associated hereditary spastic paraplegia.
Article in Nature communications, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 22 citations in OpenAlex.
- Review
- CRISPR/Cas9 loss-of-function screen in a neuronal model of AP-4 deficiency identifies ATG9A trafficking modulators.JCI insight · 2026Article
- Diagnostic Utility of the ATG9A Ratio in AP-4-Associated Hereditary Spastic Paraplegia.Annals of clinical and translational neurology · 2026Article
- Longitudinal Dynamics of Plasma Neurofilament Light Chain in Hereditary Spastic Paraplegia Type 11 (HSP-SPG11) and Type 15 (HSP-ZFYVE26).Movement disorders : official journal of the Movement Disorder Society · 2026Article
- Hereditary spastic paraplegia: from decades of therapy to future innovations.Therapeutic advances in neurological disorders · 2026Review
- A comprehensive update on the application of high-throughput fluorescence imaging for novel drug discovery.Expert opinion on drug discovery · 2025Review
- A High-Throughput Inhibitor Screen Targeting CLAG3 Export and Membrane Insertion on Human Erythrocytes Infected with Malaria Parasites.Pathogens (Basel, Switzerland) · 2025Article
- The Spastic Paraplegia-Centers of Excellence Research Network (SP-CERN): Clinical Trial Readiness for Hereditary Spastic Paraplegia.Neurology. Genetics · 2025Article
- Restoring adapter protein complex 4 function with small molecules: an in silico approach to spastic paraplegia 50.Protein science : a publication of the Protein Society · 2025Article
- An update on autophagy disorders.Journal of inherited metabolic disease · 2025Review
- Pre-clinical development of AP4B1 gene replacement therapy for hereditary spastic paraplegia type 47.EMBO molecular medicine · 2024Article
Corrections and comments
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Authors and funding
19 authors at 3 institutions in 3 countries.
Funding
Abstract
Unbiased phenotypic screens in patient-relevant disease models offer the potential to detect therapeutic targets for rare diseases. In this study, we developed a high-throughput screening assay to identify molecules that correct aberrant protein trafficking in adapter 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, BCH-HSP-C01, 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 potential mechanisms of action of BCH-HSP-C01. 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 studies.
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