論文 - 詳細
| RRC ID | 83852 |
|---|---|
| 著者 | Mora N, Slot EFJ, Lewandowski V, Menafra MP, Mallik M, van Lith P, Sijlmans C, van Bakel N, Ignatova Z, Storkebaum E. |
| タイトル | Glycyl-tRNA sequestration is a unifying mechanism underlying GARS1-associated peripheral neuropathy. |
| ジャーナル | 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. |
| 巻・号 | 53(6) |
| 公開日 | 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 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
|
| 最多言及媒体 | Bluesky |
| 各媒体での言及数の合計 | 6 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.5 |
| リソース情報 | |
| ショウジョウバエ | 6778R-1 |