Emerging mechanisms of aminoacyl-tRNA synthetase mutations in recessive and dominant human disease

Abstract

Aminoacyl-tRNA synthetases (ARSs) are responsible for charging amino acids to cognate tRNA molecules, which is the essential first step of protein translation. Interestingly, mutations in genes encoding ARS enzymes have been implicated in a broad spectrum of human inherited diseases. Bi-allelic mutations in ARSs typically cause severe, early-onset, recessive diseases that affect a wide range of tissues. The vast majority of these mutations show loss-of-function effects and impair protein translation. However, it is not clear how a subset cause tissue-specific phenotypes. In contrast, dominant ARS-mediated diseases specifically affect the peripheral nervous system-most commonly causing axonal peripheral neuropathy-and usually manifest later in life. These neuropathies are linked to heterozygosity for missense mutations in five ARS genes, which points to a shared mechanism of disease. However, it is not clear if a loss-of-function mechanism or a toxic gain-of-function mechanism is responsible for ARS-mediated neuropathy, or if a combination of these mechanisms operate on a mutation-specific basis. Here, we review our current understanding of recessive and dominant ARS-mediated disease. We also propose future directions for defining the molecular mechanisms of ARS mutations toward designing therapies for affected patient populations.

Figure 1

Potential mechanisms of ARS-related recessive disease. (A) Two wild-type ARS alleles supply cells with the requisite charged tRNA for protein translation. (B) Two loss-of-function ARS alleles severely reduce the amount of charged tRNA available for translation, which impairs protein production. Uncharged tRNA is either degraded or binds to GCN2, which phosphorylates eIF2α and inhibits global translation. In both panels, dimeric enzymes functioning in the cytoplasm are shown for simplicity; however, please note that some ARS enzymes act as monomers and that some effects apply to mitochondrial translation.

Figure 2

Potential mechanisms of ARS-related dominant axonal neuropathy. Neurons are illustrated with the cell body on the left and the axon extending to the right. A wild-type neuron (A) has functional ARS activity (green dimers) facilitating protein translation. There is appropriate NRP1 (orange transmembrane protein) and Trk signaling (blue transmembrane protein). YARS translocates to the nucleus upon oxidative stress and binds TRIM28 (blue), potentially changing the regulation of DNA damage response genes. Proposed mechanisms of ARS-mediated peripheral neuropathy are represented in (B); see text for details. Neuronal function may be compromised by impaired protein translation due to an unknown function of mutant ARS (red subunits) and/or a depletion in available charged tRNA from a significant reduction of aminoacylation activity. For peripheral neuropathy related to GARS mutations, mutant GARS may interfere with NRP1 signaling by preventing VEGFA (magenta) from binding to NRP1. In developing sensory neurons, mutant GARS may also act as a ligand for Trk receptors, aberrantly activating Trk signaling. For peripheral neuropathy related to YARS mutations, increased mutant YARS binding to TRIM28 (blue) may change the expression of DNA damage response genes.