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

Author

Listed:
  • Afshin Saffari

    (Boston Children’s Hospital, Harvard Medical School
    Heidelberg University Hospital)

  • Barbara Brechmann

    (Boston Children’s Hospital, Harvard Medical School)

  • Cedric Böger

    (Boston Children’s Hospital, Harvard Medical School)

  • Wardiya Afshar Saber

    (Boston Children’s Hospital, Harvard Medical School)

  • Hellen Jumo

    (Boston Children’s Hospital, Harvard Medical School
    Boston Children’s Hospital, Harvard Medical School)

  • Dosh Whye

    (Boston Children’s Hospital, Harvard Medical School)

  • Delaney Wood

    (Boston Children’s Hospital, Harvard Medical School)

  • Lara Wahlster

    (Boston Children’s Hospital & Dana-Farber Cancer Institute, Harvard Medical School)

  • Julian E. Alecu

    (Boston Children’s Hospital, Harvard Medical School)

  • Marvin Ziegler

    (Boston Children’s Hospital, Harvard Medical School)

  • Marlene Scheffold

    (Boston Children’s Hospital, Harvard Medical School)

  • Kellen Winden

    (Boston Children’s Hospital, Harvard Medical School)

  • Jed Hubbs

    (Boston Children’s Hospital, Harvard Medical School)

  • Elizabeth D. Buttermore

    (Boston Children’s Hospital, Harvard Medical School)

  • Lee Barrett

    (Boston Children’s Hospital, Harvard Medical School)

  • Georg H. H. Borner

    (Max-Planck-Institute of Biochemistry)

  • Alexandra K. Davies

    (Max-Planck-Institute of Biochemistry
    University of Manchester)

  • Darius Ebrahimi-Fakhari

    (Boston Children’s Hospital, Harvard Medical School
    Boston Children’s Hospital, Harvard Medical School)

  • Mustafa Sahin

    (Boston Children’s Hospital, Harvard Medical School
    Boston Children’s Hospital, Harvard Medical School)

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.

Suggested Citation

  • Afshin Saffari & Barbara Brechmann & Cedric Böger & Wardiya Afshar Saber & Hellen Jumo & Dosh Whye & Delaney Wood & Lara Wahlster & Julian E. Alecu & Marvin Ziegler & Marlene Scheffold & Kellen Winden, 2024. "High-content screening identifies a small molecule that restores AP-4-dependent protein trafficking in neuronal models of AP-4-associated hereditary spastic paraplegia," Nature Communications, Nature, vol. 15(1), pages 1-22, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-023-44264-1
    DOI: 10.1038/s41467-023-44264-1
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    References listed on IDEAS

    as
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