| RRC ID |
83852
|
| Author |
Mora N, Slot EFJ, Lewandowski V, Menafra MP, Mallik M, van Lith P, Sijlmans C, van Bakel N, Ignatova Z, Storkebaum E.
|
| Title |
Glycyl-tRNA sequestration is a unifying mechanism underlying GARS1-associated peripheral neuropathy.
|
| Journal |
Nucleic Acids Res
|
| Abstract |
Dominantly inherited mutations in eight cytosolic aminoacyl-tRNA synthetase genes cause hereditary motor and sensory neuropathy, characterized by degeneration of peripheral motor and sensory axons. We previously identified a pathogenic gain-of-toxic function mechanism underlying peripheral neuropathy (PN) caused by heterozygous mutations in the GARS1 gene, encoding glycyl-tRNA synthetase (GlyRS). Specifically, PN-mutant GlyRS variants sequester tRNAGly, which depletes the cellular tRNAGly pool, leading to insufficient glycyl-tRNAGly available to the ribosome and consequently ribosome stalling at glycine codons. Given that GlyRS functions as a homodimer, a subset of PN-GlyRS mutations might alternatively cause peripheral neuropathy through a dominant negative loss-of-function mechanism. To explore this possibility, we here generated three novel PN-GlyRS Drosophila models expressing human PN-GlyRS (hGlyRS) variants that do not alter the overall GlyRS protein charge (S211F and H418R) or the single reported PN-GlyRS variant that renders the GlyRS protein charge more negative (K456Q). High-level expression of hGlyRS-K456Q did not induce peripheral neuropathy and the K456Q variant does not affect aminoacylation activity, suggesting that K456Q is not a pathogenic mutation. Expression of hGlyRS-S211F or hGlyRS-H418R in Drosophila did induce peripheral neuropathy and de novo protein synthesis defects. Genetic and biochemical evidence indicates that these phenotypes were attributable to tRNAGly sequestration rather than a dominant negative mechanism. Our data identify tRNAGly sequestration as a unifying pathogenic mechanism underlying PN-GlyRS. Thus, elevating tRNAGly levels may constitute a therapeutic approach for all PN-GlyRS patients, irrespective of their disease-causing mutation.
|
| Volume |
53(6)
|
| Published |
2025-3-20
|
| DOI |
10.1093/nar/gkaf201
|
| PII |
8090311
|
| PMID |
40119731
|
| PMC |
PMC11928938
|
| MeSH |
Animals
Disease Models, Animal
Drosophila / genetics
Drosophila melanogaster / genetics
Drosophila melanogaster / metabolism
Glycine-tRNA Ligase* / genetics
Glycine-tRNA Ligase* / metabolism
Humans
Mutation
Peripheral Nervous System Diseases* / genetics
Peripheral Nervous System Diseases* / metabolism
RNA, Transfer, Gly* / genetics
RNA, Transfer, Gly* / metabolism
Ribosomes / genetics
Ribosomes / metabolism
|
| IF |
11.502
|
| Resource |
| Drosophila |
6778R-1 |
