PXD068839 is an
original dataset announced via ProteomeXchange.
Dataset Summary
| Title | Therapeutic rescue of pathogenic asparaginyl-tRNA synthetase alleles |
| Description | Pathogenic alleles in the cytoplasmic asparaginyl-tRNA synthetase (NARS1) are associated with infant and juvenile onset disease, with no current disease-specific treatments. We developed a tractable human cell system to study disease-causing NARS1 alleles that can be adapted to investigate NARS1 and other aaRS alleles. We found that two dominant NARS1 nonsense alleles, R534X and R522X, cause a cytotoxic phenotype and elicit the integrated stress response (ISR). Proteomic and phenotypic changes were rescued by asparagine supplementation in the human cell model. Asparagine supplementation completely restored cell proliferation defects in patient-derived fibroblasts and prevented activation of the integrated stress response. We tested therapeutic cognate tRNA supplementation, which reduced cytotoxicity of pathogenic NARS1 alleles, but did not ameliorate activation of the ISR. A GCN2 inhibitor suppressed ISR activation and reduced cytotoxicity but did not restore changes to the proteome caused by the NARS1 nonsense alleles. The data reveal molecular and cellular defects caused by pre-mature termination codons in NARS1 alleles and indicate amino acid supplementation as a feasible therapeutic approach for NARS1 disease. |
| HostingRepository | PRIDE |
| AnnounceDate | 2026-06-19 |
| AnnouncementXML | Submission_2026-06-19_09:09:50.682.xml |
| DigitalObjectIdentifier | https://doi.org/10.6019/PXD068839 |
| ReviewLevel | Peer-reviewed dataset |
| DatasetOrigin | Original dataset |
| RepositorySupport | Supported dataset by repository |
| PrimarySubmitter | Kyle Hoffman |
| SpeciesList | scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606; |
| ModificationList | monohydroxylated residue; deamidated residue; iodoacetamide derivatized residue |
| Instrument | timsTOF Pro |
Dataset History
| Revision | Datetime | Status | ChangeLog Entry |
|---|
| 0 | 2025-09-25 15:16:18 | ID requested | |
| ⏵ 1 | 2026-06-19 09:09:51 | announced | |
Publication List
Keyword List
| submitter keyword: integrated stress response,asparaginyl-tRNA synthetase, nonsense alleles |
Contact List
| Ilka Heinemann |
|---|
| contact affiliation | Department of Biochemistry, The University of Western Ontario, London, Ontario, Canada |
| contact email | iheinema@uwo.ca |
| lab head | |
| Kyle Hoffman |
|---|
| contact affiliation | Bioinformatics Solutions Inc. |
| contact email | khoffman@bioinfor.com |
| dataset submitter | |
Full Dataset Link List
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/2026/06/PXD068839 |
| PRIDE project URI |
Repository Record List
[ + ]
[ - ]
- PRIDE
- PXD068839
- Label: PRIDE project
- Name: Therapeutic rescue of pathogenic asparaginyl-tRNA synthetase alleles
