Aspartate--tRNA ligase, mitochondrial

DARS2 (aspartate–tRNA ligase, mitochondrial) catalyzes the aminoacylation of aspartate to tRNA(Asp) as part of mitochondrial protein synthesis (UniProt: Q6PI48). The enzyme functions in mitochondrial translation, a process essential for energy metabolism and cellular respiration. Mutations in DARS2 are associated with leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL; MIM 611105), a progressive autosomal recessive neurological disorder characterized by cerebellar ataxia, spasticity, and dorsal column dysfunction (UniProt: Q6PI48).

In Alzheimer's disease, DARS2 is upregulated in post-mortem AD brain tissue compared to age-matched controls (mean log2 fold-change +0.47; Chaparral AD proteomics). This upregulation was detected via TMT-labeled quantitative proteomics across subcellular fractions. The increased expression may reflect compensatory mitochondrial translation responses or altered bioenergetic demands in the degenerating AD brain, consistent with mounting evidence that mitochondrial dysfunction contributes to AD pathogenesis.