TRNA overexpression rescues peripheral neuropathy caused by mutations in tRNA synthetase
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ABSTRACT:
PROVIDER: PRJNA673697 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12960824.fastq.gz | Fastqsanger.gz | |||
| SRR12960825.fastq.gz | Fastqsanger.gz |
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Project description:Heterozygous mutations in six tRNA synthetase genes cause Charcot-Marie-Tooth (CMT) peripheral neuropathy. CMT-mutant glycyl- or tyrosyl-tRNA synthetases inhibit global protein synthesis by an unknown mechanism, independent of aminoacylation activity. We report that tRNAGly overexpression rescues protein synthesis and peripheral neuropathy phenotypes in Drosophila and mouse models of CMT caused by glycyl-tRNA synthetase (GlyRS) mutations (CMT2D). Kinetic experiments revealed that CMT-mutant GlyRS bind tRNAGly, but display markedly slow release rates. This tRNAGly sequestration may deplete the cellular tRNAGly pool, leading to insufficient glycyl-tRNAGly supply to the ribosome and translation deficit.
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Project description:Heterozygous mutations in six transfer RNA (tRNA) synthetase genes cause Charcot-Marie-Tooth (CMT) peripheral neuropathy. CMT mutant tRNA synthetases inhibit protein synthesis by an unknown mechanism. We found that CMT mutant glycyl-tRNA synthetases bound tRNAGly but failed to release it, resulting in tRNAGly sequestration. This sequestration potentially depleted the cellular tRNAGly pool, leading to insufficient glycyl-tRNAGly supply to the ribosome. Accordingly, we found ribosome stalling at glycine codons and activation of the integrated stress response (ISR) in affected motor neurons. Moreover, transgenic overexpression of tRNAGly rescued protein synthesis, peripheral neuropathy, and ISR activation in Drosophila and mouse CMT disease type 2D (CMT2D) models. Conversely, inactivation of the ribosome rescue factor GTPBP2 exacerbated peripheral neuropathy. Our findings suggest a molecular mechanism for CMT2D, and elevating tRNAGly levels may thus have therapeutic potential.
| S-EPMC8856733 | biostudies-literature
Project description:Charcot-Marie-Tooth disease (CMT) is a length-dependent peripheral neuropathy. The aminoacyl-tRNA synthetases constitute the largest protein family implicated in CMT. Aminoacyl-tRNA synthetases are predominantly cytoplasmic, but are also present in the nucleus. Here we show that a nuclear function of tyrosyl-tRNA synthetase (TyrRS) is implicated in a Drosophila model of CMT. CMT-causing mutations in TyrRS induce unique conformational changes, which confer capacity for aberrant interactions with transcriptional regulators in the nucleus, leading to transcription factor E2F1 hyperactivation. Using neuronal tissues, we reveal a broad transcriptional regulation network associated with wild-type TyrRS expression, which is disturbed when a CMT-mutant is expressed. Pharmacological inhibition of TyrRS nuclear entry with embelin reduces, whereas genetic nuclear exclusion of mutant TyrRS prevents hallmark phenotypes of CMT in the Drosophila model. These data highlight that this translation factor may contribute to transcriptional regulation in neurons, and suggest a therapeutic target for CMT.
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Project description:Aminoacyl-tRNA synthetases are the largest protein family implicated in Charcot-Marie-Tooth disease (CMT), the most common inherited peripheral neuropathy that is currently incurable. These essential enzymes catalyze the attachment of amino acids to their cognate tRNAs, thereby enabling the protein biosynthesis in every cell. Surprisingly, loss of aminoacylation is not a prerequisite for CMT to occur, suggesting a disease mechanism associated with a gain of neurotoxic function. Via an unbiased genetic modifier screen in a Drosophila model of tyrosyl-tRNA synthetase (YARS) -induced CMT, we established a link between the tRNA-ligase and regulators of actin cytoskeleton. By investigating the interactome of YARS in cellulo we found this synthetase to be enriched in protein complexes containing actin and actin-modifying proteins. Follow up in vitro and in vivo studies demonstrated that YARS itself has not only actin binding- but also actin-bundling properties independent of its aminoacylation function. These non-canonical activities are evolutionary conserved and contribute to the organization of actin cytoskeleton in Drosophila neurons and in patient-derived cells. An enzymatically active YARSCMT mutant caused stronger actin bundling in vitro, disorganization of actin bundle-rich stress fibers in patient-derived cells and impaired multiple actin-based steps of the synaptic vesicle cycle in fly neurons. Genetic modulation of the F-actin organization state restored synaptic vesicle mobility and rescued hallmark electrophysiological and morphological features in the neurons of fruit flies expressing different YARSCMT mutations. Thus, we uncover a role of tyrosyl-tRNA synthetase in actin organization that is implicated in the CMT neuropathy.
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Project description:The Synthetase Sequestration Model (SSM) is a simplified translation model that considers explicitly two main steps in the process of tRNA aminoacylation: first, the tRNA is bound by the aminoacyl tRNA synthetase, and in a second step, the amino acid is attached to the tRNA. The tRNA then participates in the translation reaction, becoming deacylated as a result. The tRNA exists in states bound, charged and uncharged. In the bound state, the tRNA is bound to the synthetase but uncharged, i.e., the tRNA is sequestered by the synthetase. The model predicts how the balance between the three different tRNA states (empty, bound and charged) changes depending on aminoacyl tRNA synthetase availability.
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Project description:Transcriptional dysregulation by a nucleus-localized aminoacyl-tRNA synthetase is associated with Charcot-Marie-Tooth neuropathy
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