PXD042950

PXD042950 is an original dataset announced via ProteomeXchange.

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
Description	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 adaptor 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.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_06:27:43.178.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Alexandra Davies
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2023-06-13 11:34:18	ID requested
1	2024-01-26 12:58:42	announced
⏵ 2	2024-10-22 06:27:44	announced	2024-10-22: Updated project metadata.

10.1038/s41467-023-44264-1;

Saffari A, Brechmann B, B, ö, ger C, Saber WA, Jumo H, Whye D, Wood D, Wahlster L, Alecu JE, Ziegler M, Scheffold M, Winden K, Hubbs J, Buttermore ED, Barrett L, Borner GHH, Davies AK, Ebrahimi-Fakhari D, Sahin M, 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, 15(1):584(2024) [pubmed]

submitter keyword: Human, autophagy, iPSC, drug screen, protein trafficking, HSP

Georg H.
contact affiliation	Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany
contact email	borner@biochem.mpg.de
lab head
Alexandra Davies
contact affiliation	University of Manchester
contact email	alexandra.davies-2@manchester.ac.uk
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2024/01/PXD042950

PRIDE project URI

• PRIDE
  1. PXD042950
     1. Label: PRIDE project
     2. Name: High-Content Screening Identifies A Small Molecule That Restores AP-4-dependent Protein Trafficking In Neuronal Models Of AP-4-Associated Hereditary Spastic Paraplegia