High-content screening identifies a small molecule that restores AP-4-dependent protein trafficking in neuronal models of AP-4-associated hereditary spastic paraplegia
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-...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-44264-1 |
| _version_ | 1797349878694674432 |
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| author | 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 Mustafa Sahin |
| author_facet | 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 Mustafa Sahin |
| author_sort | Afshin Saffari |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-08T12:36:45Z |
| format | Article |
| id | doaj.art-b52e18bceed849439f7ec10f0de5714b |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-08T12:36:45Z |
| publishDate | 2024-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-b52e18bceed849439f7ec10f0de5714b2024-01-21T12:25:57ZengNature PortfolioNature Communications2041-17232024-01-0115112210.1038/s41467-023-44264-1High-content screening identifies a small molecule that restores AP-4-dependent protein trafficking in neuronal models of AP-4-associated hereditary spastic paraplegiaAfshin Saffari0Barbara Brechmann1Cedric Böger2Wardiya Afshar Saber3Hellen Jumo4Dosh Whye5Delaney Wood6Lara Wahlster7Julian E. Alecu8Marvin Ziegler9Marlene Scheffold10Kellen Winden11Jed Hubbs12Elizabeth D. Buttermore13Lee Barrett14Georg H. H. Borner15Alexandra K. Davies16Darius Ebrahimi-Fakhari17Mustafa Sahin18Department of Neurology & F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical SchoolDepartment of Neurology & F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical SchoolDepartment of Neurology & F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical SchoolDepartment of Neurology & F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical SchoolDepartment of Neurology & F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical SchoolRosamund Stone Zander Translational Neuroscience Center, Boston Children’s Hospital, Harvard Medical SchoolRosamund Stone Zander Translational Neuroscience Center, Boston Children’s Hospital, Harvard Medical SchoolDepartment of Hematology & Oncology, Boston Children’s Hospital & Dana-Farber Cancer Institute, Harvard Medical SchoolDepartment of Neurology & F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical SchoolDepartment of Neurology & F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical SchoolDepartment of Neurology & F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical SchoolDepartment of Neurology & F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical SchoolRosamund Stone Zander Translational Neuroscience Center, Boston Children’s Hospital, Harvard Medical SchoolRosamund Stone Zander Translational Neuroscience Center, Boston Children’s Hospital, Harvard Medical SchoolRosamund Stone Zander Translational Neuroscience Center, Boston Children’s Hospital, Harvard Medical SchoolDepartment of Proteomics and Signal Transduction, Max-Planck-Institute of BiochemistryDepartment of Proteomics and Signal Transduction, Max-Planck-Institute of BiochemistryDepartment of Neurology & F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical SchoolDepartment of Neurology & F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical SchoolAbstract 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.https://doi.org/10.1038/s41467-023-44264-1 |
| spellingShingle | 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 Mustafa Sahin 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 |
| title | High-content screening identifies a small molecule that restores AP-4-dependent protein trafficking in neuronal models of AP-4-associated hereditary spastic paraplegia |
| title_full | High-content screening identifies a small molecule that restores AP-4-dependent protein trafficking in neuronal models of AP-4-associated hereditary spastic paraplegia |
| title_fullStr | High-content screening identifies a small molecule that restores AP-4-dependent protein trafficking in neuronal models of AP-4-associated hereditary spastic paraplegia |
| title_full_unstemmed | High-content screening identifies a small molecule that restores AP-4-dependent protein trafficking in neuronal models of AP-4-associated hereditary spastic paraplegia |
| title_short | High-content screening identifies a small molecule that restores AP-4-dependent protein trafficking in neuronal models of AP-4-associated hereditary spastic paraplegia |
| title_sort | high content screening identifies a small molecule that restores ap 4 dependent protein trafficking in neuronal models of ap 4 associated hereditary spastic paraplegia |
| url | https://doi.org/10.1038/s41467-023-44264-1 |
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