The integrated stress response contributes to tRNA synthetase–associated peripheral neuropathy

Abstract

Defeating peripheral neuropathy The mechanisms underlying peripheral neuropathies are not well understood. Spaulding et al . studied mouse models of the inherited Charcot-Marie-Tooth (CMT) disease, which is caused by mutations in transfer RNA (tRNA) synthetases. Changes in gene expression and the rate of protein synthesis in neurons in the spinal cord triggered the cell stress response activated by the protein sensor GCN2. When GCN2 was genetically deleted or inhibited with drugs, the stress response was blocked, and the neuropathy was much milder. Zuko et al . found that mutant glycyl-tRNA synthetases bind tRNA Gly but fail to release it, thus depleting the cellular tRNA Gly pool. This process caused stalling of translating ribosomes on glycine codons and activated the integrated stress response. Transgenic tRNA Gly overexpression prevented peripheral neuropathy and protein synthesis defects in mouse and fruit fly models. Thus, elevating tRNA Gly levels or targeting GCN2 may have therapeutic potential for this currently untreatable disease (see the Perspective by Mellado and Willis). —SMH

Drosophila Models for Charcot–Marie–Tooth Neuropathy Related to Aminoacyl-tRNA Synthetases

“…The depletion of general tRNA Gly pool induces ribosome stalling and leads to activation of the integrated stress response (ISR) [68]. In a parallel study using Gars CMT and Yars CMT mouse models, Spaulding et al, performed cell type specific transcriptional and translational profiling demonstrating GCN2-dependent ISR activation specifically in α motor neurons and in a subset of sensory neurons [101]. The general control nonderepressible 2 protein (GCN2) is a serine-threonine kinase playing a key role in modulating the ISR as a response to nutrient deprivation and sensing amino acid deficiency through binding to uncharged tRNA [101].…”

“…In a parallel study using Gars CMT and Yars CMT mouse models, Spaulding et al, performed cell type specific transcriptional and translational profiling demonstrating GCN2-dependent ISR activation specifically in α motor neurons and in a subset of sensory neurons [101]. The general control nonderepressible 2 protein (GCN2) is a serine-threonine kinase playing a key role in modulating the ISR as a response to nutrient deprivation and sensing amino acid deficiency through binding to uncharged tRNA [101]. Genetic or pharmacological inhibition of GCN2 blocked the IRS and alleviated the peripheral neuropathy phenotype in different GARS1 CMT mice models [101].…”

“…The general control nonderepressible 2 protein (GCN2) is a serine-threonine kinase playing a key role in modulating the ISR as a response to nutrient deprivation and sensing amino acid deficiency through binding to uncharged tRNA [101]. Genetic or pharmacological inhibition of GCN2 blocked the IRS and alleviated the peripheral neuropathy phenotype in different GARS1 CMT mice models [101]. This suggest GCN2 as an effective therapeutic strategy that could potentially be applied to other CMT-associated aaRS.…”

An Integrated Approach to Studying Rare Neuromuscular Diseases Using Animal and Human Cell-Based Models

“…Furthermore, though the Gars /CMT2D mouse models accurately recapitulate the human disease, it also remains to be determined whether the same ISR mechanism is active in human motor and sensory neurons. Circulating levels of one prominently upregulated, secreted ATF4 target gene, GDF15, were elevated in patients with tRNA synthetase mutations; however, GDF15 was also elevated in PMP22 /CMT1A patients ( Spaulding et al, 2021 ). This is interesting and may suggest GDF15 is a general biomarker for multiple forms of CMT, but it makes the direct relevance to ISR activation in the tRNA synthetase mutations less definitive.…”

“…In an analogous case of neurodegeneration caused by ribosome stalling during translation elongation due to a combination of a tRNA Ala mutation and loss of GTPBP2, which rescues stalled ribosomes from mRNAs, the inhibition of GCN2 and the ISR is detrimental, exacerbating the associated neurodegeneration ( Ishimura et al, 2014 ; Ishimura et al, 2016 ). However, in the case of Gars /CMT2D mouse models, genetically deleting or pharmacologically inhibiting GCN2 not only eliminates ISR activation, but also greatly mitigates the severity of the neuropathy phenotype ( Spaulding et al, 2021 ). That an experimental drug was also effective in mitigating neuropathy in the Gars mice speaks to the translational potential of inhibiting GCN2 to treat dominant tRNA synthetase-associated peripheral neuropathies.…”