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 Swipe
Afshin Saffari
,
Barbara Brechmann
,
Cedric Böger
,
Wardiya Afshar Saber
,
Hellen Jumo
,
Dosh Whye
,
Delaney Wood
,
Lara Wahlster
,
Julian E. Alecu
,
M. L. ZIEGLER
,
Marlene Scheffold
,
Kellen D. Winden
,
Jed L. Hubbs
,
Elizabeth D. Buttermore
,
Lee Barrett
,
Georg H. H. Borner
,
Alexandra K. Davies
,
Darius Ebrahimi‐Fakhari
,
Mustafa Şahin
·
YOU?
·
· 2024
· Open Access
·
· DOI: https://doi.org/10.1038/s41467-023-44264-1
YOU?
·
· 2024
· Open Access
·
· DOI: https://doi.org/10.1038/s41467-023-44264-1
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.
Related Topics
Concepts
Hereditary spastic paraplegia
High-content screening
Biology
Computational biology
Small molecule
Induced pluripotent stem cell
Phenotype
Cell biology
Bioinformatics
Embryonic stem cell
Genetics
Gene
Cell
Metadata
- Type
- article
- Language
- en
- Landing Page
- https://doi.org/10.1038/s41467-023-44264-1
- https://www.nature.com/articles/s41467-023-44264-1.pdf
- OA Status
- gold
- Cited By
- 18
- References
- 92
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4390935776
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
-
https://openalex.org/W4390935776Canonical identifier for this work in OpenAlex
- DOI
-
https://doi.org/10.1038/s41467-023-44264-1Digital Object Identifier
- Title
-
High-content screening identifies a small molecule that restores AP-4-dependent protein trafficking in neuronal models of AP-4-associated hereditary spastic paraplegiaWork title
- Type
-
articleOpenAlex work type
- Language
-
enPrimary language
- Publication year
-
2024Year of publication
- Publication date
-
2024-01-17Full publication date if available
- Authors
-
Afshin Saffari, Barbara Brechmann, Cedric Böger, Wardiya Afshar Saber, Hellen Jumo, Dosh Whye, Delaney Wood, Lara Wahlster, Julian E. Alecu, M. L. ZIEGLER, Marlene Scheffold, Kellen D. Winden, Jed L. Hubbs, Elizabeth D. Buttermore, Lee Barrett, Georg H. H. Borner, Alexandra K. Davies, Darius Ebrahimi‐Fakhari, Mustafa ŞahinList of authors in order
- Landing page
-
https://doi.org/10.1038/s41467-023-44264-1Publisher landing page
- PDF URL
-
https://www.nature.com/articles/s41467-023-44264-1.pdfDirect link to full text PDF
- Open access
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YesWhether a free full text is available
- OA status
-
goldOpen access status per OpenAlex
- OA URL
-
https://www.nature.com/articles/s41467-023-44264-1.pdfDirect OA link when available
- Concepts
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Hereditary spastic paraplegia, High-content screening, Biology, Computational biology, Small molecule, Induced pluripotent stem cell, Phenotype, Cell biology, Bioinformatics, Embryonic stem cell, Genetics, Gene, CellTop concepts (fields/topics) attached by OpenAlex
- Cited by
-
18Total citation count in OpenAlex
- Citations by year (recent)
-
2025: 10, 2024: 8Per-year citation counts (last 5 years)
- References (count)
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92Number of works referenced by this work
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10Other works algorithmically related by OpenAlex
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| abstract_inverted_index.ATG9A. | 59 |
| abstract_inverted_index.action | 117 |
| abstract_inverted_index.define | 122 |
| abstract_inverted_index.detect | 12 |
| abstract_inverted_index.future | 145 |
| abstract_inverted_index.models | 7 |
| abstract_inverted_index.study, | 20 |
| abstract_inverted_index.adapter | 36 |
| abstract_inverted_index.complex | 38 |
| abstract_inverted_index.correct | 31 |
| abstract_inverted_index.disease | 6, 90 |
| abstract_inverted_index.induced | 96 |
| abstract_inverted_index.library | 73 |
| abstract_inverted_index.models, | 91 |
| abstract_inverted_index.protein | 33, 37, 58 |
| abstract_inverted_index.results | 121 |
| abstract_inverted_index.screens | 3 |
| abstract_inverted_index.spastic | 50 |
| abstract_inverted_index.targets | 14 |
| abstract_inverted_index.Abstract | 0 |
| abstract_inverted_index.Unbiased | 1 |
| abstract_inverted_index.aberrant | 32 |
| abstract_inverted_index.analysis | 67 |
| abstract_inverted_index.compound | 133 |
| abstract_inverted_index.identify | 28 |
| abstract_inverted_index.multiple | 89 |
| abstract_inverted_index.neurons. | 100 |
| abstract_inverted_index.restored | 85 |
| abstract_inverted_index.screened | 70 |
| abstract_inverted_index.studies. | 146 |
| abstract_inverted_index.automated | 65 |
| abstract_inverted_index.autophagy | 57 |
| abstract_inverted_index.compound, | 82 |
| abstract_inverted_index.delineate | 113 |
| abstract_inverted_index.developed | 22 |
| abstract_inverted_index.diseases. | 17 |
| abstract_inverted_index.diversity | 72 |
| abstract_inverted_index.important | 141 |
| abstract_inverted_index.including | 92 |
| abstract_inverted_index.molecular | 123 |
| abstract_inverted_index.molecules | 29, 77 |
| abstract_inverted_index.pathology | 87 |
| abstract_inverted_index.pipeline, | 68 |
| abstract_inverted_index.potential | 10, 114 |
| abstract_inverted_index.proteomic | 110 |
| abstract_inverted_index.providing | 140 |
| abstract_inverted_index.screening | 25 |
| abstract_inverted_index.treatment | 136 |
| abstract_inverted_index.approaches | 111 |
| abstract_inverted_index.hereditary | 49 |
| abstract_inverted_index.identified | 79 |
| abstract_inverted_index.integrated | 107 |
| abstract_inverted_index.mechanisms | 115 |
| abstract_inverted_index.microscopy | 62 |
| abstract_inverted_index.orthogonal | 104 |
| abstract_inverted_index.paraplegia | 51 |
| abstract_inverted_index.phenotypic | 2 |
| abstract_inverted_index.regulators | 124 |
| abstract_inverted_index.strategies | 105 |
| abstract_inverted_index.deficiency, | 41, 139 |
| abstract_inverted_index.fibroblasts | 94 |
| abstract_inverted_index.pluripotent | 97 |
| abstract_inverted_index.therapeutic | 13 |
| abstract_inverted_index.trafficking | 34, 128 |
| abstract_inverted_index.BCH-HSP-C01, | 83 |
| abstract_inverted_index.BCH-HSP-C01. | 119 |
| abstract_inverted_index.cell-derived | 99 |
| abstract_inverted_index.characterize | 130 |
| abstract_inverted_index.high-content | 61 |
| abstract_inverted_index.prototypical | 45 |
| abstract_inverted_index.characterized | 52 |
| abstract_inverted_index.intracellular | 126 |
| abstract_inverted_index.transcriptomic | 108 |
| abstract_inverted_index.childhood-onset | 48 |
| abstract_inverted_index.high-throughput | 24 |
| abstract_inverted_index.mislocalization | 54 |
| abstract_inverted_index.multiparametric | 103 |
| abstract_inverted_index.patient-derived | 93 |
| abstract_inverted_index.patient-relevant | 5 |
| abstract_inverted_index.proof-of-concept | 142 |
| cited_by_percentile_year.max | 99 |
| cited_by_percentile_year.min | 98 |
| corresponding_author_ids | https://openalex.org/A5041028445 |
| countries_distinct_count | 2 |
| institutions_distinct_count | 19 |
| corresponding_institution_ids | https://openalex.org/I1288882113, https://openalex.org/I136199984 |
| citation_normalized_percentile.value | 0.97508383 |
| citation_normalized_percentile.is_in_top_1_percent | False |
| citation_normalized_percentile.is_in_top_10_percent | True |