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Glycyl-tRNA sequestration is a unifying mechanism underlying GARS1-associated peripheral neuropathy
Natalia Mora1, Erik F J Slot1, Vanessa Lewandowski2
1Molecular Neurobiology Laboratory, Donders Institute for Brain, Cognition and Behaviour and Faculty of Science, Radboud University, 6525AJ Nijmegen, the Netherlands.
Nucleic Acids Research
|March 22, 2025
Summary
Mutations in glycyl-tRNA synthetase (GlyRS) cause peripheral neuropathy (PN) by sequestering tRNAGly. This study confirms tRNAGly sequestration as the unifying mechanism for PN-GlyRS, suggesting tRNA level modulation as a therapy.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Hereditary motor and sensory neuropathies are linked to mutations in aminoacyl-tRNA synthetase genes.
- Heterozygous mutations in GARS1 (glycyl-tRNA synthetase) cause peripheral neuropathy (PN) via tRNAGly sequestration and ribosome stalling.
Purpose of the Study:
- To investigate if a dominant-negative loss-of-function mechanism contributes to PN caused by GARS1 mutations.
- To clarify the pathogenic mechanism of specific human GlyRS (hGlyRS) variants (S211F, H418R, K456Q) in Drosophila models.
Main Methods:
- Generated Drosophila models expressing three human PN-GlyRS variants (hGlyRS-S211F, hGlyRS-H418R, hGlyRS-K456Q).
- Assessed for peripheral neuropathy and de novo protein synthesis defects.
- Performed genetic and biochemical analyses to determine the pathogenic mechanism.
Main Results:
- hGlyRS-K456Q expression did not cause neuropathy or affect aminoacylation, indicating it's not pathogenic.
- Expression of hGlyRS-S211F and hGlyRS-H418R induced peripheral neuropathy and protein synthesis defects in Drosophila.
- Evidence supports tRNAGly sequestration, not a dominant-negative effect, as the cause of these phenotypes.
Conclusions:
- tRNAGly sequestration is the unifying pathogenic mechanism for peripheral neuropathy caused by GARS1 mutations.
- Therapeutic strategies aimed at increasing tRNAGly levels could benefit all patients with PN-GlyRS.
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