Expression of the Neuronal tRNA n-Tr20 Regulates Synaptic Transmission and Seizure Susceptibility

Abstract

Highlights d n-Tr20 loss reduces seizure sensitivity and alters synaptic transmission d Ribosome stalling caused by loss of n-Tr20 activates the integrated stress response d n-Tr20 loss suppresses mTORC1 signaling, contributing to altered neurotransmission d Modulation of translation initiation pathways is a conserved response to tRNA loss

GTPBP1 resolves paused ribosomes to maintain neuronal homeostasis

“…Neuron death in B6J- Gtpbp2 nmf205 / nmf205 (B6J- Gtpbp2 -/- ) mice is a result of the epistatic interaction between the null mutation in Gtpbp2 and a hypomorphic mutation present in the B6J strain that disrupts processing of the brain-specific, nuclear encoded tRNA, n-Tr20. n-Tr20 is widely expressed in neurons and is the most highly expressed of the five tRNA Arg UCU genes in the brain, and the B6J-associated mutation reduces the pool of available tRNA Arg UCU ( Ishimura et al, 2014 ; Kapur et al, 2020 ). In the absence of Gtpbp2 , translating ribosomes in the cerebellum exhibit prolonged pauses at AGA codons, suggesting GTPBP2 acts as a ribosome-rescue factor to resolve codon-specific ribosome pausing that occurs when the available pool of cognate tRNAs is limited.…”

Hijacking tRNAs From Translation: Regulatory Functions of tRNAs in Mammalian Cell Physiology

“…Above and beyond its role in viral infection, recent studies have proved that the fluctuation of tRNA repertoire plays a crucial role in shaping the cellular proteomic landscape. Dysregulation of individual tRNAs contributes to the onset and severity of various diseases, including metastatic and non-metastatic cancers, Huntington disease, cystic fibrosis, seizures, multiple myeloma, and neurodegeneration (Pavon-Eternod et al, 2009Zhou et al, 2009;Girstmair et al, 2013;Ishimura et al, 2014;Birch et al, 2016;Goodarzi et al, 2016;Kirchner et al, 2017;Zhang et al, 2018b;Kapur et al, 2020; Figure 2).…”

“…It is elusive how the expression of a single tRNA isodecoder is regulated in a tissue-specific manner, because the promoter sequences used by PolIII are identical among the five members of the tRNA Arg UCU family. Interestingly, loss of wild-type (wt) n-Tr20 alters signaling pathways regulating transcription and translation, leading to changes in synaptic transmission and reduced seizure susceptibility (Kapur et al, 2020). Deletion of wt n-Tr20 regulates the transcription of 236 genes and splicing of 377 genes, demonstrating the role of a single tRNA isodecoder at different stages of RNA metabolism (Kapur et al, 2020).…”

GTPBP1 resolves paused ribosomes to maintain neuronal homeostasis

“…A previous study observed increased mTOR activity in epidermal stem cells upon loss of the ribosome recycling factor Pelo , and suppression of mTOR signaling partially restored cellular defects in vivo (Liakath-Ali et al, 2018). We recently observed that the relatively low levels of ribosome pausing that occur upon tRNA deficiency (with normal levels of GTPBP1 and GTPBP2) can lead to mTORC1 inhibition and alter neuronal physiology (Kapur et al, 2020). Together, these data demonstrate that elongation defects may lead to hyper- or hypoactivity of mTOR signaling and these changes in mTORC1 appear to negatively modulate cellular homeostasis and survival.…”

“…Neuron death in B6J- Gtpbp2 nmf205/nmf205 (B6J- Gtpbp2 -/- ) mice is a result of the epistatic interactions between the loss-of-function mutation in Gtpbp2 and a hypomorphic mutation present in the B6J strain that disrupts processing of the brain-specific, nuclear encoded tRNA, n-Tr20. n-Tr20 is widely expressed in neurons and is the most highly expressed member of the five tRNA Arg UCU genes in brain, and the B6J-associated mutation reduces the pool of available tRNA Arg UCU (Kapur et al, 2020). In the absence of Gtpbp2 , translating ribosomes in the cerebellum exhibit prolonged pauses at AGA codons, suggesting GTPBP2 acts as a ribosome rescue factor to resolve codon-specific ribosome pausing occurring when the available pool of cognate tRNAs is limited.…”