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Free keywords:
Animals
Aspartate-tRNA Ligase/*deficiency/genetics
Brain Stem/growth & development/metabolism/pathology
Cell Survival/genetics
Cerebellar Ataxia/diagnostic imaging/*genetics/metabolism/pathology
Cerebellum/growth & development/metabolism/pathology
Humans
Lactic Acid/metabolism
Leukoencephalopathies/diagnostic imaging/*genetics/pathology
Magnetic Resonance Imaging
Mice
Mitochondria/genetics/metabolism
Mitochondrial Diseases/diagnostic imaging/*genetics/pathology
Mutation/genetics
Myelin Sheath/*genetics
Neurons/*metabolism/pathology
Purkinje Cells/metabolism/pathology
Spinal Cord/growth & development/metabolism
Abstract:
Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation disorder (LBSL) arises from mutations in mitochondrial aspartyl-tRNA synthetase (DARS2) gene. The disease has a childhood or juvenile-onset and is clinically characterized by cerebellar ataxia, cognitive decline and distinct morphological abnormalities upon magnetic resonance imaging. We previously demonstrated that neurons and not adult myelin-producing cells are specifically sensitive to DARS2 loss, hence likely the primary culprit in LBSL disorder. We used conditional Purkinje cell (PCs)-specific Dars2 deletion to elucidate further the cell-type-specific contribution of this class of neurons to the cerebellar impairment observed in LBSL. We show that DARS2 depletion causes a severe mitochondrial dysfunction concomitant with a massive loss of PCs by the age of 15 weeks, thereby rapidly deteriorating motor skills. Our findings conclusively show that DARS2 is indispensable for PC survival and highlights the central role of neuroinflammation in DARS2-related PC degeneration.
