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Therapeutic rescue of pathogenic asparaginyl-tRNA synthetase alleles

ABSTRACT: 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.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Kyle Hoffman

LAB HEAD: Ilka Heinemann

PROVIDER: PXD068839 | Pride | 2026-06-19

REPOSITORIES: pride

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			Action	DRS
	db.mzidentml_1_1_0.xml	Mzid
	db.mzidentml_1_2_0.xml	Mzid
	db.pep.xml	Pepxml
	s25009-1-20250501_Slot1-03_1_5473.d.mzxml	Mzxml
	s25009-1-20250501_Slot1-03_1_5473.d.zip	Other

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