2. Academic Validation
  3. High-content screening identifies a small molecule that restores AP-4-dependent protein trafficking in neuronal models of AP-4-associated hereditary spastic paraplegia

High-content screening identifies a small molecule that restores AP-4-dependent protein trafficking in neuronal models of AP-4-associated hereditary spastic paraplegia

  • Nat Commun. 2024 Jan 17;15(1):584. doi: 10.1038/s41467-023-44264-1.
Afshin Saffari 1 2,  Barbara Brechmann 1,  Cedric Böger 1,  Wardiya Afshar Saber 1,  Hellen Jumo 1 3,  Dosh Whye 3,  Delaney Wood 3,  Lara Wahlster 4,  Julian E Alecu 1,  Marvin Ziegler 1,  Marlene Scheffold 1,  Kellen Winden 1,  Jed Hubbs 3,  Elizabeth D Buttermore 3,  Lee Barrett 3,  Georg H H Borner 5,  Alexandra K Davies 5 6,  Darius Ebrahimi-Fakhari 7 8,  Mustafa Sahin 1 3
Affiliations

Affiliations

  • 1 Department of Neurology & F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
  • 2 Division of Child Neurology and Inherited Metabolic Diseases, Heidelberg University Hospital, Heidelberg, Germany.
  • 3 Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
  • 4 Department of Hematology & Oncology, Boston Children's Hospital & Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02115, USA.
  • 5 Department of Proteomics and Signal Transduction, Max-Planck-Institute of Biochemistry, Martinsried, 82152, Germany.
  • 6 School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, M13 9PT, UK.
  • 7 Department of Neurology & F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA. darius.ebrahimi-fakhari@childrens.harvard.edu.
  • 8 Movement Disorders Program, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA. darius.ebrahimi-fakhari@childrens.harvard.edu.
PMID: 38233389 DOI: 10.1038/s41467-023-44264-1
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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