TY - JOUR TI - GTPBP1 resolves paused ribosomes to maintain neuronal homeostasis AU - Terrey, Markus AU - Adamson, Scott I AU - Gibson, Alana L AU - Deng, Tianda AU - Ishimura, Ryuta AU - Chuang, Jeffrey H AU - Ackerman, Susan L A2 - Ron, David A2 - Zoghbi, Huda Y A2 - Ron, David A2 - Sonenberg, Nahum VL - 9 PY - 2020 DA - 2020/11/13 SP - e62731 C1 - eLife 2020;9:e62731 DO - 10.7554/eLife.62731 UR - https://doi.org/10.7554/eLife.62731 AB - Ribosome-associated quality control pathways respond to defects in translational elongation to recycle arrested ribosomes and degrade aberrant polypeptides and mRNAs. Loss of a tRNA gene leads to ribosomal pausing that is resolved by the translational GTPase GTPBP2, and in its absence causes neuron death. Here, we show that loss of the homologous protein GTPBP1 during tRNA deficiency in the mouse brain also leads to codon-specific ribosome pausing and neurodegeneration, suggesting that these non-redundant GTPases function in the same pathway to mitigate ribosome pausing. As observed in Gtpbp2-/- mice (Ishimura et al., 2016), GCN2-mediated activation of the integrated stress response (ISR) was apparent in the Gtpbp1-/- brain. We observed decreased mTORC1 signaling which increased neuronal death, whereas ISR activation was neuroprotective. Our data demonstrate that GTPBP1 functions as an important quality control mechanism during translation elongation and suggest that translational signaling pathways intricately interact to regulate neuronal homeostasis during defective elongation. KW - tRNA-Arg-TCT-4-1 KW - ribosome stalling KW - cerebellum KW - granule cells KW - hippocampus KW - retina JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -