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Modeling Mitochondrial Disease Using Brain Organoids: A Focus on Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like Episodes
08:56

Modeling Mitochondrial Disease Using Brain Organoids: A Focus on Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like Episodes

Published on: October 10, 2025

Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation is associated with

Laura van Berge1, Stephanie Dooves, Carola G M van Berkel

  • 1Department of Child Neurology, VU University Medical Center, Amsterdam, The Netherlands. l.vanberge@vumc.nl

The Biochemical Journal
|October 26, 2011
PubMed

Insights

Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation (LBSL) is a white matter disorder caused by DARS2 gene mutations. Cell-type-specific splicing defects in neuronal cells explain LBSL

Area of Science:

  • Genetics
  • Neuroscience
  • Molecular Biology

Background:

  • Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation (LBSL) is an autosomal recessive white matter disorder.
  • It presents with progressive cerebellar ataxia, spasticity, and dorsal column dysfunction, with characteristic MRI findings.
  • LBSL is caused by mutations in the DARS2 gene, encoding mitochondrial aspartyl-tRNA synthetase (mtAspRS).

Purpose of the Study:

  • To investigate the mechanism behind the selective vulnerability of specific white matter tracts in LBSL.
  • To understand why DARS2 mutations, encoding a ubiquitously expressed protein, lead to specific neurological deficits.

Main Methods:

  • Utilized a splicing reporter construct to assess the impact of DARS2 mutations on mRNA splicing.
  • Compared the effects of mutations in neural (especially neuronal) and non-neural cell lines.
  • Analyzed the efficiency of correct exon 3 inclusion in mtAspRS mRNA in different cell types.

Main Results:

  • DARS2 mutations affecting DARS2 gene splicing had a greater impact on exon 3 exclusion in neural cell lines, particularly neuronal cells, compared to non-neural cells.
  • Correct inclusion of exon 3 in mtAspRS mRNA was less efficient in neural cells, most notably in neuronal cells.
  • These cell-type-specific splicing alterations were observed to be more pronounced in neuronal cells.

Conclusions:

  • The findings suggest that cell-type-specific differences in splicing efficiency and sensitivity to DARS2 mutations contribute to the selective white matter tract involvement in LBSL.
  • This study provides a molecular explanation for the neuropathology observed in LBSL patients, linking gene mutations to specific cellular mechanisms.

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