tRNA overexpression rescues peripheral neuropathy caused by mutations in tRNA synthetase

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

“…Nervous system (nSyb-GAL4) [43] hGARS1 E71G, G240R, G526R Glutamatergic neurons (OK371-GAL4) [44,67,68] GFS morphological and electrophysiological deficits…”

“…Class IV multidendritic sensory neurons (ppk-GAL4) [44,68] Rough eye dGARS P234KY Eye photoreceptor cell (GMR-GAL4)…”

“…In a recent study, Zuko et al dissected the molecular mechanism by which GARS1 CMT mutations inhibit global protein translation [68]. They demonstrated that GARS1 CMT interferes with translation elongation, rather than translation initiation, as overexpression of initiation factors (such as eIF4E, constitutively active S6 kinase or poly(A) binding protein) as well as knock-down of translation inhibition factors (such as Protein kinase RNA-like endoplasmic reticulum kinase (Perk) or 4EBP) neither rescued nor enhanced the translational defects observed in GARS1 G240R D. melanogaster model [68]. Rather, the GARS1 CMT mutant proteins sequester tRNA Gly leading to ribosome stalling at Gly codons and activation of the integrated stress response (ISR), ultimately shutting down the global protein synthesis [68].…”

“…They demonstrated that GARS1 CMT interferes with translation elongation, rather than translation initiation, as overexpression of initiation factors (such as eIF4E, constitutively active S6 kinase or poly(A) binding protein) as well as knock-down of translation inhibition factors (such as Protein kinase RNA-like endoplasmic reticulum kinase (Perk) or 4EBP) neither rescued nor enhanced the translational defects observed in GARS1 G240R D. melanogaster model [68]. Rather, the GARS1 CMT mutant proteins sequester tRNA Gly leading to ribosome stalling at Gly codons and activation of the integrated stress response (ISR), ultimately shutting down the global protein synthesis [68]. Notably, overexpression of tRNA Gly partially rescued all phenotypes in their GARS1 CMT D. melanogaster models (e.g translational defects, larval muscle denervation, larval sensory neuron morphology defects, adult motor deficits, developmental lethality and shortened lifespan) in a dose-dependent manner [68].…”

“…Rather, the GARS1 CMT mutant proteins sequester tRNA Gly leading to ribosome stalling at Gly codons and activation of the integrated stress response (ISR), ultimately shutting down the global protein synthesis [68]. Notably, overexpression of tRNA Gly partially rescued all phenotypes in their GARS1 CMT D. melanogaster models (e.g translational defects, larval muscle denervation, larval sensory neuron morphology defects, adult motor deficits, developmental lethality and shortened lifespan) in a dose-dependent manner [68]. Importantly, the rescue effect is cognate tRNAspecific, as overexpression of tRNA Gly had no effect on the neurodegenerative phenotypes in YARS1 CMT D. melanogaster models [68].…”