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

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, Jed Hubbs, Elizabeth D. Buttermore, Lee Barrett, Georg H. H. Borner, Alexandra K. Davies, Darius Ebrahimi-Fakhari () and Mustafa Sahin
Additional contact information
Afshin Saffari: Boston Children’s Hospital, Harvard Medical School
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
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
Darius Ebrahimi-Fakhari: Boston Children’s Hospital, Harvard Medical School
Mustafa Sahin: Boston Children’s Hospital, Harvard Medical School

Nature Communications, 2024, vol. 15, issue 1, 1-22

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-023-44264-1

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