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Last update 08 May 2025

DARS2

Last update 08 May 2025

Basic Info

Synonyms

Aspartate--tRNA ligase, mitochondrial, Aspartyl-tRNA synthetase, aspartyl-tRNA synthetase 2, mitochondrial

+ [4]

Introduction

Catalyzes the attachment of aspartate to tRNA(Asp) in a two-step reaction: aspartate is first activated by ATP to form Asp-AMP and then transferred to the acceptor end of tRNA(Asp).

Drugs associated with DARS2

WO2024081687

Patent Mining

Target

DARS2

Mechanism-

Active Org.

University of Maryland School of Medicine [+2]

Originator Org.

Kennedy Krieger Institute, Inc. [+2]

Active Indication

Nutritional and Metabolic Diseases

Inactive Indication-

Drug Highest PhaseDiscovery

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with DARS2

100 Translational Medicine associated with DARS2

0 Patents (Medical) associated with DARS2

112

Literatures (Medical) associated with DARS2

01 Jun 2025·Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease

Aminolevulinate/iron exposure elicited Nrf-2-mediated cytoprotection in DARS2 deficient fibroblasts with impaired energy and antioxidant metabolisms

Article

Author: Schwartz, Philip H ; Abdenur, Jose E ; Huang, Wei-Lin ; Eichwald, Tuany ; Latini, Alexandra ; Gazanfari, Milad ; Stover, Alexander

Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation (LBSL) is a disorder caused by mutations in the mitochondrial aspartyl-tRNA synthetase gene DARS2, which compromises mitochondrial protein translation. The typical presentation is juvenile in onset with gradually progressive spasticity and ataxia. Only palliative treatment is available for LBSL individuals. Here we showed that the use of the Food and Drug Administration-approved heme precursors, aminolevulinate plus ferrous iron (ALA/Fe), can result in a novel pharmacological treatment that increases energy status in DARS2 deficient cells. The marked mitochondrial and antioxidant deficiencies observed in fibroblasts from two LBSL-affected brothers, harboring intron-2 (c.228-17C > G) and intron-5 (c.492 + 2 T > C) DARS2 mutations, were rescued by ALA/Fe exposure, and the use of dexamethasone, a known Nrf-2 inhibitor, blocked the positive effects of ALA/Fe. Altogether, this study showed that fibroblasts can be used as a biological system to identify potential new treatments for LBSL that can reduce morbidity and mortality, and that the activation of Nrf-2-mediated cytoprotection can be targeted for the treatment of LBSL and other mitochondrial diseases.

01 Feb 2025·Journal of Neurology

Diagnosis of hereditary ataxias: a real-world single center experience

Article

Author: Ceravolo, Roberto ; Cori, Ludovica ; Bernardini, Clara ; Palermo, Giovanni ; Rocchi, Anna ; Fogli, Antonella ; Siciliano, Gabriele ; Meli, Adriana ; Gerfo, Annalisa Lo ; Cecchi, Giulia ; Mancuso, Michelangelo ; Montano, Vincenzo ; Siniscalchi, Antonio ; Maltomini, Rossella ; Lopriore, Piervito ; Caligo, Maria Adelaide

OBJECTIVEThis study aims to evaluate our experience in the diagnosis of hereditary ataxias (HAs), to analyze data from a real-world scenario.STUDY DESIGNThis is a retrospective, cross-sectional, descriptive study conducted at a single Italian adult neurogenetic outpatient clinic, in 147 patients affected by ataxia with a suspicion of hereditary forms, recruited from November 1999 to February 2024. A stepwise approach for molecular diagnostics was applied: targeted gene panel (TP) next-generation sequencing (NGS) and/or clinical exome sequencing (CES) were performed in the case of inconclusive first-line genetic testing, such as short tandem repeat expansions (TREs) testing for most common spinocerebellar ataxias (SCA1-3, 6-8,12,17, DRPLA), other forms [Fragile X-associated tremor/ataxia syndrome (FXTAS), Friedreich ataxia (FRDA) and mitochondrial DNA-related ataxia, RFC1-related ataxia/CANVAS] or inconclusive phenotype-guided specific single gene sequencing.RESULTA definitive diagnosis was reached in 36.7% of the cases. TREs testing was diagnostic in 30.4% of patients. The three most common TREs ataxias were FRDA (36.1%), SCA2 (27.8%), and RFC1-related ataxia/CANVAS (11.1%). In five patients, the molecular diagnosis was achieved by single gene sequencing and causative mutations were identified in POLG (2), SACS (1), DARS2 (1), MT-ATP6 (1). Of 94 patients with a suspicion of HAs of indeterminate genetic origin, 68 underwent new molecular evaluation using the NGS approach. In 28 of these cases, CES was performed after the TP sequencing resulted negative. In 13 patients, the diagnosis was achieved by NGS approach. In 7 of these 13 patients, the diagnosis was made by CES. Genes mutations identified as causative of HAs were found in SPG7 (4), SACS (1), CACNA1A (1), CACNA1G (1), EEF2 (1), PRKCG (1), KCNC3 (1), ADCK3 (1), SYNE1 (1), ITPR1 (1). A positive family history of ataxia and early onset of symptoms were associated with a higher likelihood of obtaining a definite diagnosis.CONCLUSIONThe molecular diagnosis of HAs remains a significant challenge for neurologists. Our data indicate that, in most cases, a diagnosis of HA can be established through first line genetic testing, particularly TREs testing. However, for patients with a clinical diagnosis of HA who do not achieve a molecular diagnosis through initial genetic tests, the use of NGS proves to be a valuable tool, providing a definitive diagnosis in approximately 20% of cases. Therefore, when feasible in clinical practice, integrating NGS testing, especially exome sequencing, into the diagnostic decision-making process for unsolved cases is crucial.

27 Jan 2025·International Journal of Biological Sciences

DARS2 Promotes Bladder Cancer Progression by Enhancing PINK1-Mediated Mitophagy

Article

Author: Zheng, Zaosong ; Tan, Wanlong ; Chen, Chen ; Li, Fei ; Wang, Zihuan ; Su, Hang ; Wang, Qiong ; Zhang, Jinge ; Zhao, Shanchao ; Huang, Yuan ; Chen, Haiyong ; Li, Dongqing ; Hou, Lina ; Deng, Xiaolin ; Chen, Zhe-Sheng

Globally, bladder cancer is the tenth most common cancer. Mitophagy, a critical process regulating mitochondrial quantity and quality, has attracted increasing attention for its pivotal function in cancer. Nonetheless, its roles and underlying mechanisms in bladder cancer are yet to be elucidated. Therefore, in this study, 16 mitophagy-related genes were screened to construct a robust prognostic model with exceptional predictive accuracy for the outcomes of patients with bladder cancer. Of these genes, DARS2 was identified as a key regulator that significantly affected cancer progression. The findings established that DARS2 promoted the G1-to-S phase transition by upregulating CDK4 expression, thereby suppressing cellular senescence and driving cell proliferation. In addition, DARS2 augmented PINK1 expression, leading to increased PINK1-mediated mitophagy. Both in vitro and in vivo experiments confirmed that DARS2 inhibited cellular senescence and facilitated tumor progression by enhancing PINK1-mediated mitophagy. The observations from this study have provided novel insights into the multifaceted roles of DARS2-mediated mitophagy in bladder cancer. Targeting DARS2 and its regulation of mitophagy is a promising therapeutic strategy to improve the outcomes for patients with bladder cancer.

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DARS2

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