Journal
NEURON
Volume 108, Issue 1, Pages 193-+Publisher
CELL PRESS
DOI: 10.1016/j.neuron.2020.07.023
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Funding
- NIH [R01 NS094637, R37 NS031349]
- NIH-NCI CCSG [P30 014195]
- Helmsley Center for Genomic Medicine
- Mass Spectrometry Core of the Salk Institute
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The mammalian genome has hundreds of nuclear-encoded tRNAs, but the contribution of individual tRNA genes to cellular and organismal function remains unknown. Here, we demonstrate that mutations in a neuronally enriched arginine tRNA, n-Tr20, increased seizure threshold and altered synaptic transmission. n-Tr20 expression also modulated seizures caused by an epilepsy-linked mutation in Gabrg2, a gene encoding a GABAA receptor subunit. Loss of n-Tr20 altered translation initiation by activating the integrated stress response and suppressing mTOR signaling, the latter of which may contribute to altered neurotransmission in mutant mice. Deletion of a highly expressed isoleucine tRNA similarly altered these signaling pathways in the brain, suggesting that regulation of translation initiation is a conserved response to tRNA loss. Our data indicate that loss of a single member of a tRNA family results in multiple cellular phenotypes, highlighting the disease-causing potential of tRNA mutations.
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