Ribosome 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 eIF2 (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 eIF2 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. SOURCE: Jeffrey Chuang (jeff.chuang@jax.org) -  The Jackson Laboratory for Genomic Medicine

Pluto Bioinformatics

GSE79929: Examination of gene expression in cerebellum of mouse strains B6J, B6J-nmf205-/-, B6J-Gcn2-/- and B6J-nmf205-/-;Gcn2-/-.