ENAGenomicsMultiomicsComputational Biology, The Jackson Laboratory for Genomic Medicinehttps://www.ebi.ac.uk/ena/browser/view/PRJNA317432Mus musculusxref:PubMed:27085088Ribosome stalling during translation has recently been shown to cause neurodegeneration, yet the signaling pathways triggered by stalled elongation complexes are unknown. To investigate these pathways we analyzed the brain of B6J-nmf205-/- mice in which neuronal elongation complexes are stalled at AGA codons due to deficiencies in a tRNA Arg(UCU) tRNA and GTPBP2, a mammalian ribosome rescue factor. Increased levels of phosphorylation of eIF2α (Ser51) were detected prior to neurodegeneration in these mice and transcriptome analysis demonstrated activation of ATF4, a key transcription factor in the integrated stress response (ISR) pathway. Genetic experiments showed that this pathway was activated by the eIF2α kinase, GCN2, in an apparent deacylated tRNA-independent fashion. Further we found that the ISR attenuates neurodegeneration in B6J-nmf205-/- mice, underscoring the importance of cellular and stress context on the outcome of activation of this pathway. These results demonstrate the critical interplay between translation elongation and initiation in regulating neuron survival during cellular stress. Overall design: Examination of gene expression in cerebellum and hippocampus for 4 mice strains derived from C57BL/6J (B6J) strain. Microarray data was performed for 3 week and 5 week old mice in both cerebellum and hippocampus for B6J and B6J-nmf205-/- three replicates each. RNA-Seq data was perform on cerebellum of mice 3 weeks old, three replicates for each genotype: B6J, B6J-nmf205-/-, B6J-Gcn2-/- and B6J-nmf205-/- Gcn2-/-.ENAammon gyrus, Horn, Cornu ammonis, corpus cerebelli, Ammon, Ammon horn fields, Laboratory, formatio hippocampi, Proper, Mus domesticus, epencephalon-1, ammon horn, mouse, Hippocampus Propers, Gene, Ammon Horn, Hippocampal Formation, hippocampus proper, C57BL6J, House Mouse, Cerebella, seahorse, Subiculums, archipallium, Hippocampal, Formations, House, Mus, Mus musculus domesticus, major hippocampus, Ammon's Horn, Cornu Ammonis, Mice, Subiculum, Hippocampus Proper, Hippocampus, cornu ammonis, Mus musculus, hippocampus proprius, Ammon's, Ammon's horn, Parencephalons, Gene Expressions, Propers, Corpus Cerebelli, Swiss, mice, Swiss Mouse, CNS - Brain - Hippocampus (MMHCC), House Mice, Swiss Mice, hippocampus major, Expressions, Ammons Horn, domesticus, Laboratory Mice, Parencephalon, hippocampus, parencephalon, infratentorial region, Cerebellums, primal cortex, Ammons horn, Mouse, Expression, house mouse, Hippocampal Formations, Laboratory Mouse, nmf205., FormationMus musculus, Laboratory Mice., House, Mus, Laboratory, Swiss, Mus domesticus, mouse, Mus musculus domesticus, Swiss Mouse, mouse <Mus musculus>, Mouse, House Mice, Swiss Mice, house mouse, Mice, Laboratory Mouse, House Mouse, mice C57BL/6xCBA/CaJ hybrid, domesticus, Mus muscarisfalseMus musculusExamination of gene expression in cerebellum and hippocampus for mouse C57BL/6J WT and nmf205-/-2025-09-242016-06-17PRJNA317432GSE799261009027085088