In vivo characterization of the aspartyl-tRNA synthetase DARS: homing in on the leukodystrophy HBSL

Dominik Fröhlich, Alexandra K. Suchowerska, Ziggy H. T. Spencer, Georg von Jonquieres, Claudia B. Klugmann, Andre Bongers, Fabien Delerue, Holly Stefen, Lars M. Ittner, Thomas Fath, Gary D. Housley, Matthias Klugmann

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Background: The recently diagnosed leukodystrophy Hypomyelination with Brain stem and Spinal cord involvement and Leg spasticity (HBSL) is caused by mutations of the cytoplasmic aspartyl-tRNA synthetase gene DARS. The physiological role of DARS in translation is to accurately pair aspartate with its cognate tRNA. Clinically, HBSL subjects show a distinct pattern of hypomyelination and develop progressive leg spasticity, variable cognitive impairment and epilepsy. To elucidate the underlying pathomechanism, we comprehensively assessed endogenous DARS expression in mice. Additionally, aiming at creating the first mammalian HBSL model, we genetically engineered and phenotyped mutant mice with a targeted Dars locus. Results: DARS, although expressed in all organs, shows a distinct expression pattern in the adult brain with little immunoreactivity in macroglia but enrichment in neuronal subpopulations of the hippocampus, cerebellum, and cortex. Within neurons, DARS is mainly located in the cell soma where it co-localizes with other components of the translation machinery. Intriguingly, DARS is also present along neurites and at synapses, where it potentially contributes to local protein synthesis. Dars-null mice are not viable and die before embryonic day 11. Heterozygous mice with only one functional Dars allele display substantially reduced DARS levels in the brain; yet these mutants show no gross abnormalities, including unchanged motor performance. However, we detected reduced pre-pulse inhibition of the acoustic startle response indicating dysfunction of attentional processing in Dars+/− mice. Conclusions: Our results, for the first time, show an in-depth characterization of the DARS tissue distribution in mice, revealing surprisingly little uniformity across brain regions or between the major neural cell types. The complete loss of DARS function is not tolerated in mice suggesting that the identified HBSL mutations in humans retain some residual enzyme activity. The mild phenotype of heterozygous Dars-null carriers indicates that even partial restoration of DARS levels would be therapeutically relevant. Despite the fact that they do not resemble the full spectrum of clinical symptoms, the robust pre-pulse inhibition phenotype of Dars+/− mice will be instrumental for future preclinical therapeutic efficacy studies. In summary, our data is an important contribution to a better understanding of DARS function and HBSL pathology.

Original languageEnglish
Pages (from-to)24-35
Number of pages12
JournalNeurobiology of Disease
Issue numberPart A
Publication statusPublished - 1 Jan 2017
Externally publishedYes

Bibliographical note

Copyright the Author(s) 2016. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.


  • Aminoacyl-tRNA synthetase
  • Aspartyl-tRNA synthetase
  • DARS
  • HBSL
  • Leukodystrophy
  • Mouse model


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