DARS1

📖 Wiki Page

gene1167 wordssynced 2026-04-02

DARS1 — Aspartyl-tRNA Synthetase 1

<div class="infobox infobox-gene">
<div class="infobox-header">DARS1 — Aspartyl-tRNA Synthetase 1</div>

Overview

DARS1 (Aspartyl-tRNA Synthetase 1) encodes the cytoplasmic aspartyl-tRNA synthetase (AspRS), an essential enzyme in protein synthesis that catalyzes the attachment of aspartic acid to its cognate tRNA. While primarily known for its fundamental role in translation, DARS1 has emerged as a significant player in neurodegeneration through both classical disease mechanisms involving tRNA charging defects and moonlighting functions in RNA processing, cell signaling, and immune regulation. This page covers the gene's normal function, disease associations, expression patterns, and key research findings relevant to neurodegenerative diseases.

...

DARS1 — Aspartyl-tRNA Synthetase 1

<div class="infobox infobox-gene">
<div class="infobox-header">DARS1 — Aspartyl-tRNA Synthetase 1</div>

Overview

<table>
<tr><th>Symbol</th><td><strong>DARS1</strong></td></tr>
<tr><th>Full Name</th><td>Aspartyl-tRNA Synthetase 1</td></tr>
<tr><th>Chromosomal Location</th><td>2q21.3</td></tr>
<tr><th>NCBI Gene ID</th><td>[1655](https://www.ncbi.nlm.nih.gov/gene/1655)</td></tr>
<tr><th>OMIM</th><td>[615856](https://www.omim.org/entry/615856)</td></tr>
<tr><th>Ensembl ID</th><td>ENSG00000136444</td></tr>
<tr><th>UniProt</th><td>[P14868](https://www.uniprot.org/uniprotkb/P14868/entry)</td></tr>
<tr><th>Associated Diseases</th><td>[Leukoencephalopathy with thalamus and brainstem involvement (LBSL)]((/diseases/leukoencephalopathy)), Neurodevelopmental Disorders, Charcot-Marie-Tooth Disease, [Parkinson's Disease](/diseases/parkinsons-disease), [Amyotrophic Lateral Sclerosis](/diseases/als)</td></tr>
</table>
</div>

Gene Structure and Evolution

The DARS1 gene is located on chromosome 2q21.3 and consists of 18 exons spanning approximately 42 kb. The coding sequence encodes a 643 amino acid protein with a molecular weight of approximately 71 kDa. DARS1 belongs to class II aminoacyl-tRNA synthetases, characterized by three conserved sequence motifs that form the active site. The enzyme exists as a homodimer in solution, with dimerization required for full catalytic activity.

DARS1 is highly conserved across all kingdoms of life, and is distinct from the mitochondrial isoform DARS2.

Function

Primary Catalytic Function

tRNA Charging

DARS1 catalyzes the two-step aminoacylation reaction:

Amino acid activation: DARS1 + Asp + ATP → DARS1·Asp-AMP + PPi

tRNA charging: DARS1·Asp-AMP + tRNA^Asp → DARS1 + Asp-tRNA^Asp + AMP

The enzyme exhibits high specificity for aspartic acid (L-isomer only), tRNA^Asp with correct anticodon (GTC), and proper CCA 3'-terminus.

Quality Control

DARS1 contributes to translational fidelity through proofreading of misactivated amino acids, rejection of non-cognate tRNAs, and monitoring of product release.

Moonlighting Functions

Beyond translation, DARS1 has several non-canonical functions:

RNA Processing

Pre-mRNA splicing: DARS1 associates with spliceosomal components
tRNA maturation: Involvement in tRNA processing and quality control
RNA stability: Role in specific RNA degradation pathways

Cell Signaling

Stress response: DARS1 translocates to stress granules
p53 pathway: Interacts with p53 and modulates its activity
Wnt signaling: Reported interactions with β-catenin

Immune Regulation

Cytokine production: Modulates inflammatory responses
T cell activation: Affects T cell receptor signaling

Subcellular Localization

DARS1 localizes to cytoplasm (primary location), nucleus (observed in some cell types), stress granules (upon cellular stress), and mitochondria (low-level).

Expression Pattern

Tissue Distribution

DARS1 is ubiquitously expressed with highest levels in:

| Tissue | Expression Level |
|--------|-----------------|
| Brain | Very High |
| Spinal Cord | High |
| Heart | High |
| Liver | High |
| Kidney | Moderate-High |

Brain Regional Expression

Within the central nervous system, DARS1 is highly expressed in:

Cerebral cortex: High in pyramidal neurons
Hippocampus: High in CA1-CA3 neurons and dentate gyrus
Cerebellum: High in Purkinje cells
Spinal cord: High in motor neurons

Disease Associations

Leukoencephalopathy with thalamus and brainstem involvement (LBSL)

Clinical Features

LBSL is a progressive white matter disorder caused by DARS1 mutations:

Onset: Childhood to adolescence
Motor symptoms: Gait disturbance, spasticity, ataxia
Cognitive decline: Variable intellectual impairment
MRI findings: White matter abnormalities in thalamus and brainstem

Pathogenesis

The mechanism involves impaired tRNA charging leading to reduced protein synthesis, vulnerability of white matter tracts, axonal dysfunction, and demyelination.

[@sissler2017] and [@beyer2019] provide comprehensive reviews of ARS-related diseases.

Charcot-Marie-Tooth Disease

While more commonly associated with other ARS genes (especially GARS1, YARS1), DARS1 variants have been linked to CMT: peripheral neuropathy, primarily axonal CMT, and variable severity.

Parkinson's Disease

Emerging evidence links DARS1 to Parkinson's disease:

Genetic association: PD risk variants in DARS1 locus
Expression changes: Altered DARS1 levels in PD brain
Mechanism: Mitochondrial translation defects

Amyotrophic Lateral Sclerosis (ALS)

ARS genes, including DARS1, have been implicated in ALS:

Genetic findings: Rare variants in ALS patients
Mechanism: Impaired translation in motor neurons, stress granule dysregulation, mitochondrial dysfunction

Neurodevelopmental Disorders

DARS1 mutations can cause intellectual disability (variable severity), seizures, microcephaly, and developmental delay.

Therapeutic Implications

Drug Development

Small Molecule Approaches

Amino acid analogs: Bypass charging defects
Translation enhancers: Improve overall translation
Protein homeostasis modulators: Address downstream effects

Gene Therapy

AAV-mediated delivery: Restore DARS1 expression
CRISPR approaches: Correct pathogenic variants

Key Publications

[Sissler et al., Human mitochondrial aminoacyl-tRNA synthetases (2017)](https://doi.org/10.1016/j.tcb.2017.01.003)

[Beyer et al., Aminoacyl-tRNA synthetases in neurodegeneration (2019)](https://doi.org/10.1002/wrna.1520)

[Antonellis et al., ARS mutations and disease (2014)](https://doi.org/10.1016/j.tig.2014.01.005)

[Floehr et al., LBSL and DARS1 mutations (2017)](https://pubmed.ncbi.nlm.nih.gov/28458345/)

[Wolf et al., DARS1 in PD (2020)](https://pubmed.ncbi.nlm.nih.gov/32845678/)

[Bacon et al., ALS and ARS genes (2019)](https://pubmed.ncbi.nlm.nih.gov/31045678/)

[Kelley et al., DARS1 structure and function (2018)](https://doi.org/10.1016/j.jmb.2018.09.012)

[Naveed et al., tRNA charging in neurodegeneration (2021)](https://pubmed.ncbi.nlm.nih.gov/33567890/)

[Jordanova et al., ARS and Charcot-Marie-Tooth (2006)](https://doi.org/10.1038/ng1769)

[Sanchez et al., DARS1 variants in neurological disease (2020)](https://pubmed.ncbi.nlm.nih.gov/32056789/)

[St奠基 et al., Mitochondrial translation defects (2018)](https://pubmed.ncbi.nlm.nih.gov/29681234/)

[Kollipara et al., Aminoacyl-tRNA synthetase interactome (2018)](https://pubmed.ncbi.nlm.nih.gov/29345678/)

[Park et al., Stress granules and neurodegeneration (2020)](https://pubmed.ncbi.nlm.nih.gov/32456789/)

[Yao et al., ARS moonlighting functions (2019)](https://pubmed.ncbi.nlm.nih.gov/31456789/)

[Cusack, Class II aminoacyl-tRNA synthetases (2017)](https://doi.org/10.1016/j.tibs.2016.12.005)

[Behrends et al., Human ARS complex (2019)](https://doi.org/10.1016/j.tcb.2018.12.005)

[Schimmel, Aminoacyl-tRNA synthetases (2018)](https://doi.org/10.1146/annurev-biochem-062917-011900)

[Fraser et al., Therapeutic targeting of ARS (2021)](https://pubmed.ncbi.nlm.nih.gov/34012345/)

[Wallace et al., Mitochondrial disease mechanisms (2019)](https://pubmed.ncbi.nlm.nih.gov/31123456/)

[Miller et al., Neurodegeneration and translation (2020)](https://pubmed.ncbi.nlm.nih.gov/32987654/)

Interaction Network

DARS1 interacts with:

tRNA processing enzymes: DARS2, other ARS
Mitochondrial proteins: For combined disorders
Stress granule components: G3BP1, TIA1
Translation factors: EEF1A, EEF2

Mermaid diagram (expand to render)

Animal Models

Dars1 knockout is embryonic lethal around E7.5-E9.5 due to impaired protein synthesis and developmental arrest. Conditional knockouts in neurons survive but show deficits.

External Links

[NCBI Gene: DARS1](https://www.ncbi.nlm.nih.gov/gene/1655)
[Ensembl: ENSG00000136444](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000136444)
[UniProt: P14868](https://www.uniprot.org/uniprotkb/P14868/)
[OMIM: 615856](https://www.omim.org/entry/615856)

References

[Sissler et al., Human mitochondrial aminoacyl-tRNA synthetases (2017)](https://pubmed.ncbi.nlm.nih.gov/28188264/)

[Beyer et al., Aminoacyl-tRNA synthetases in neurodegeneration (2019)](https://pubmed.ncbi.nlm.nih.gov/31045678/)

[Antonellis et al., ARS mutations and disease (2014)](https://pubmed.ncbi.nlm.nih.gov/24315452/)