Translation occurs in three steps: initiation, elongation and termination. Defects in translation elongation can result in toxic aggregation-prone and non-functional proteins that are implicated in many diseases including neurodegeneration. A foundational study by the Ackerman lab (Ishimura et al., 2016) demonstrated that impaired translation elongation promotes the repression of translation initiation, and that this feedback control has an important role in brain health. The group had previously found that ribosome stalling in mice, caused by deficiencies in the ribosome rescue factor Gtpbp2 and the nervous-system-specific tRNAArgUCU genes, leads to ageing-associated neurodegeneration (Ishimura et al., 2014). Excitingly, their 2016 study revealed that ribosome stalling in this context causes a neuroprotective suppression of translation initiation in the brain that delays the onset of neurodegeneration. Without this reduction in translation initiation, the authors demonstrate a profound acceleration and escalation of neuronal loss in the brain. I highlight three major implications of this study that, in my opinion, are the roots of now flourishing branches of the proteostasis field.

Second, this study suggested that the eIF2α kinase GCN2 can be activated by stalled ribosomes. Earlier work had demonstrated that uncharged tRNAs activate GCN2 by preferentially binding its histidyl-tRNA synthetase-like domain. Ishimura et al. showed that phosphorylation of eIF2α was dependent on GCN2, as were more than half of the gene expression changes observed in the cerebella of mice deficient in Gtpbp2 and tRNAArgUCU. However, the uncharged:charged tRNAArgUCU ratio was not altered in mutant Gtpbp2 and tRNAArgUCU mice, strongly suggesting that activation of GCN2 after ribosome stalling did not depend on uncharged tRNAs. This paradigm-shifting idea sparked a flurry of studies to identify the molecular mechanisms of GCN2 activation by ribosome stalling.