Howard Hughes Medical Institute, Department of Cellular and Molecular Medicine, Section of Neurobiology, University of California, San Diego, La Jolla, CA 92093, USA.
The Jackson Laboratory, Bar Harbor, ME 04609, USA.
Neuron. 2020 Oct 14;108(1):193-208.e9. doi: 10.1016/j.neuron.2020.07.023. Epub 2020 Aug 26.
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 GABA 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.
哺乳动物基因组中有数百种核编码 tRNA，但单个 tRNA 基因对细胞和生物体功能的贡献仍不清楚。在这里，我们证明了富含神经元的精氨酸 tRNA n-Tr20 的突变会增加癫痫发作阈值并改变突触传递。n-Tr20 的表达也调节了由 GABA 受体亚基 Gabrg2 中的癫痫相关突变引起的癫痫发作。n-Tr20 的缺失通过激活整合应激反应和抑制 mTOR 信号转导来改变翻译起始，后者可能导致突变小鼠的神经递质传递改变。高度表达的异亮氨酸 tRNA 的缺失也以类似的方式改变了大脑中的这些信号通路，这表明翻译起始的调节是对 tRNA 缺失的保守反应。我们的数据表明，单个 tRNA 家族成员的缺失会导致多种细胞表型，突出了 tRNA 突变的致病潜力。
