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

ABSTRACT: 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 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE79929 | GEO | 2016/06/15

SECONDARY ACCESSION(S): PRJNA317431

REPOSITORIES: GEO

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

Project description: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 eIF2Î± (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 eIF2alpha 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. 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-/-.

2016-06-15 | E-GEOD-79929 | biostudies-arrayexpress

Examination of gene expression in cerebellum and hippocampus for mouse C57BL/6J WT and nmf205-/-

Project description: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 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.

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Examination of gene expression in cerebellum and hippocampus for mouse C57BL/6J WT and nmf205-/-

Project description: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 eIF2Î± (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 eIF2Î± 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. 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-/-.

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Ribosome stalling induced by mutation of a CNS-specific tRNA causes neurodegeneration

Project description:In higher eukaryotes, the large numbers of nuclear-encoded tRNA genes partially ensure the robustness of cytoplasmic protein translation. Here we discover that a loss-of-function in n-Tr20, a member of the nuclear-encoded tRNA Arg UCU family that is expressed specifically in the central nervous systems leads to low but detectable levels of ribosome stalling. In the absence of GTPBP2, a novel binding partner of the ribosome recycling protein Pelota, ribosome stalling increases, leading to widespread neurodegeneration. Our results not only define GTPBP2 as a ribosome rescue factor, but also unmask the disease potential of mutations in nuclear-encoded tRNA genes. In this submission we provide ribosome footprinting data from the cerebella of four strains derived from the C57BL/6J strain with combinations of n-Tr20 and GTPBP2 mutations. Examination of ribosome stalling in cerebella from 4 mouse strains derived from the: C57BL/6J (B6J) strain. The nmf205-/- strain has a homozygous mutation in the gene GTPBP2 while the B6J strain has normal GTPBP2. The n-Tr20 J/J strain has a defect in the n-Tr20 tRNA while the n-Tr20 N/N strain has a functional n-Tr20 tRNA. The 4 strains are the 2x2 combinations of these defects and correctly functioning sequences. 2 replicates for each strain. Please note that only BAM files are included in the records since they form the basis of the study's conclusions. The raw data ribosomal RNA have been filtered and then unique reads mapping to mm10 were computed using tophat and igenome annotations.

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