Advances in Research on AARS1/AARS2-Related Disorders: A Focus on Leukodystrophies

Leukodystrophies (LDs), a group of heterogeneous genetic disorders, are characterized by selective involvement of cerebral white matter, including abnormal white matter development and/or progressive degeneration. Oligodendrocytes, astrocytes, microglia, axons, and the neurovascular unit collectively contribute to white matter homeostasis and disease progression. Recently, genomic sequencing has identified pathogenic variants in the alanyl-tRNA synthetase 1 (AARS1) and alanyl-tRNA synthetase 2, mitochondrial (AARS2) genes in LD-related phenotypes. Dysfunction of AARS1 and AARS2 proteins may impair cytosolic or mitochondrial tRNA aminoacylation, compromise editing fidelity, and disrupt mitochondrial homeostasis, which may lead to disruption of protein homeostasis, cellular stress responses, and energy failure. Alanyl-tRNA synthetase (AlaRS) impairments play an important role in the pathological processes of cytosolic and mitochondrial alanyl-tRNA synthetase-related disorders. These molecular defects are associated with characteristic neuroimaging patterns and diverse clinical manifestations observed in AARS1/AARS2-related disorders. This review summarizes current knowledge on the genetic basis, clinicopathological features, and molecular mechanisms of AARS1- and AARS2-related leukodystrophies, and discusses emerging therapeutic perspectives, with the aim of facilitating precision diagnosis and future targeted interventions.