Neuronal ablation of mt-AspRS in mice induces immune pathway activation prior to severe and progressive cortical and behavioral disruption

Nemeth, Christina L.; Tomlinson, Sophia N.; Rosen, Melissa; O'Brien, Brett; Larraza, Oscar; Jain, Mahim; Murray, Connor F.; Marx, Joel; Delannoy, Michaël; Fine, Amena Smith; Wu, Dan; Trifunović, Aleksandra; Fatemi, Ali

doi:10.1016/j.expneurol.2019.113164

Cited by 14 publications

(27 citation statements)

References 40 publications

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“…The introduction of other HBSL point mutations might produce a more accurate disease model with an early disease onset as seen in the majority of HBSL patients. Moreover, the use of a conditional knockout system will be instrumental in dissecting the contribution of Dars1 -deficiency in select organs or cell lineages similar to what has been reported for Dars2 (Aradjanski et al, 2017 ; Nemeth et al, 2020 ; Rumyantseva et al, 2020 ).…”

Section: Discussionmentioning

confidence: 90%

A Hypomorphic Dars1D367Y Model Recapitulates Key Aspects of the Leukodystrophy HBSL

Fröhlich

Mendes

Kueh

et al. 2021

Front. Cell. Neurosci.

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Hypomyelination with brain stem and spinal cord involvement and leg spasticity (HBSL) is a leukodystrophy caused by missense mutations of the aspartyl-tRNA synthetase-encoding gene DARS1. The clinical picture includes the regression of acquired motor milestones, spasticity, ataxia, seizures, nystagmus, and intellectual disabilities. Morphologically, HBSL is characterized by a distinct pattern of hypomyelination in the central nervous system including the anterior brainstem, the cerebellar peduncles and the supratentorial white matter as well as the dorsal columns and the lateral corticospinal tracts of the spinal cord. Adequate HBSL animal models are lacking. Dars1 knockout mice are embryonic lethal precluding examination of the etiology. To address this, we introduced the HBSL-causing Dars1D367Y point mutation into the mouse genome. Surprisingly, mice carrying this mutation homozygously were phenotypically normal. As hypomorphic mutations are more severe in trans to a deletion, we crossed Dars1D367Y/D367Y mice with Dars1-null carriers. The resulting Dars1D367Y/− offspring displayed a strong developmental delay compared to control Dars1D367Y/+ littermates, starting during embryogenesis. Only a small fraction of Dars1D367Y/− mice were born, and half of these mice died with hydrocephalus during the first 3 weeks of life. Of the few Dars1D367Y/− mice that were born at term, 25% displayed microphthalmia. Throughout postnatal life, Dars1D367Y/− mice remained smaller and lighter than their Dars1D367Y/+ littermates. Despite this early developmental deficit, once they made it through early adolescence Dars1D367Y/− mice were phenotypically inconspicuous for most of their adult life, until they developed late onset motor deficits as well as vacuolization and demyelination of the spinal cord white matter. Expression levels of the major myelin proteins were reduced in Dars1D367Y/− mice compared to controls. Taken together, Dars1D367Y/− mice model aspects of the clinical picture of the corresponding missense mutation in HBSL. This model will enable studies of late onset deficits, which is precluded in Dars1 knockout mice, and can be leveraged to test potential HBSL therapeutics including DARS1 gene replacement therapy.

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Section: Discussionmentioning

confidence: 90%

A Hypomorphic Dars1D367Y Model Recapitulates Key Aspects of the Leukodystrophy HBSL

Fröhlich

Mendes

Kueh

et al. 2021

Front. Cell. Neurosci.

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“…Two neuronal Dars2 cKO models have been created utilizing the Cre/LoxP system (Aradjanski et al, 2017 ; Nemeth et al, 2020 ). In both models, mice were crossed to CamKIIα Cre-driver lines, expressing Cre recombinase under control of the neuronal CamKIIα promotor.…”

Section: Mouse Models Of Diseasementioning

confidence: 99%

“…Neuronal Dars2 cKO mice displayed severe morphological and behavioral changes starting around week 24 and worsening until 28 weeks of age (Aradjanski et al, 2017 ). These morphological changes included severe brain atrophy concentrated around the forebrain cortex and hippocampal area (Aradjanski et al, 2017 ; Nemeth et al, 2020 ) and enlargements of the third and lateral ventricles, with a notable sparing of the cerebellum (Nemeth et al, 2020 ). Additionally, thinning of the corpus callosum was also noted (Aradjanski et al, 2017 ; Nemeth et al, 2020 ).…”

Section: Mouse Models Of Diseasementioning

confidence: 99%

“…These morphological changes included severe brain atrophy concentrated around the forebrain cortex and hippocampal area (Aradjanski et al, 2017 ; Nemeth et al, 2020 ) and enlargements of the third and lateral ventricles, with a notable sparing of the cerebellum (Nemeth et al, 2020 ). Additionally, thinning of the corpus callosum was also noted (Aradjanski et al, 2017 ; Nemeth et al, 2020 ). Microscopically, this is accompanied by neuronal cell death, as demonstrated by the presence of pyknotic cells and vacuoles in the affected regions at 28 weeks of age (Aradjanski et al, 2017 ).…”

Section: Mouse Models Of Diseasementioning

confidence: 99%

“…Conversely, in the other study, neuronal Dars2 cKO mice were of higher body mass than controls until 28 weeks of age, after which they were comparable to controls. In addition, neuronal Dars2 cKO mice were more active compared to controls, particularly in their explorative behavior (Nemeth et al, 2020 ). Both models displayed an increase in mitochondria number, however, the mitochondrial ultrastructure appeared normal in one model (Nemeth et al, 2020 ), while there was a loss of normal cristae in the other model indicating mitochondrial dysfunction (Aradjanski et al, 2017 ).…”

Section: Mouse Models Of Diseasementioning

confidence: 99%

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The Leukodystrophies HBSL and LBSL—Correlates and Distinctions

Muthiah

Housley

Klugmann

et al. 2021

Front. Cell. Neurosci.

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Aminoacyl-tRNA synthetases (ARSs) accurately charge tRNAs with their respective amino acids. As such, they are vital for the initiation of cytosolic and mitochondrial protein translation. These enzymes have become increasingly scrutinized in recent years for their role in neurodegenerative disorders caused by the mutations of ARS-encoding genes. This review focuses on two such genes—DARS1 and DARS2—which encode cytosolic and mitochondrial aspartyl-tRNA synthetases, and the clinical conditions associated with mutations of these genes. We also describe attempts made at modeling these conditions in mice, which have both yielded important mechanistic insights. Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is a disease caused by a range of mutations in the DARS2 gene, initially identified in 2003. Ten years later, hypomyelination with brainstem and spinal cord involvement and leg spasticity (HBSL), caused by mutations of cytosolic DARS1, was discovered. Multiple parallels have been drawn between the two conditions. The Magnetic Resonance Imaging (MRI) patterns are strikingly similar, but still set these two conditions apart from other leukodystrophies. Clinically, both conditions are characterized by lower limb spasticity, often associated with other pyramidal signs. However, perhaps due to earlier detection, a wider range of symptoms, including peripheral neuropathy, as well as visual and hearing changes have been described in LBSL patients. Both HBSL and LBSL are spectrum disorders lacking genotype to phenotype correlation. While the fatal phenotype of Dars1 or Dars2 single gene deletion mouse mutants revealed that the two enzymes lack functional redundancy, further pursuit of disease modeling are required to shed light onto the underlying disease mechanism, and enable examination of experimental treatments, including gene therapies.

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Disease models of mitochondrial aminoacyl‐tRNA synthetase defects

Tyynismaa

2023

J of Inher Metab Disea

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Mitochondrial aminoacyl‐tRNA synthetases (mtARS) are enzymes critical for the first step of mitochondrial protein synthesis by charging mitochondrial tRNAs with their cognate amino acids. Pathogenic variants in all 19 nuclear mtARS genes are now recognized as causing recessive mitochondrial diseases. Most mtARS disorders affect the nervous system, but the phenotypes range from multisystem diseases to tissue‐specific manifestations. However, the mechanisms behind the tissue specificities are poorly understood, and challenges remain in obtaining accurate disease models for developing and testing treatments. Here, some of the currently existing disease models that have increased our understanding of mtARS defects are discussed.

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Neuronal ablation of mt-AspRS in mice induces immune pathway activation prior to severe and progressive cortical and behavioral disruption

Cited by 14 publications

References 40 publications

A Hypomorphic Dars1D367Y Model Recapitulates Key Aspects of the Leukodystrophy HBSL

A Hypomorphic Dars1D367Y Model Recapitulates Key Aspects of the Leukodystrophy HBSL

The Leukodystrophies HBSL and LBSL—Correlates and Distinctions

Disease models of mitochondrial aminoacyl‐tRNA synthetase defects

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