Activation of GCN2 kinase by ribosome stalling links translation elongation with translation initiation
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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 C57BL/6J-Gtpbp2nmf205-/- mice in which neuronal elongation complexes are stalled at AGA codons due to deficiencies in a tRNAArgUCU 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 C57BL/6J-Gtpbp2nmf205-/- 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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The C57BL6/J (B6J)-nmf205 mouse model has mutations in both the translation GTPase GTPBP2 and the neuronal tRNAArgUCU genes that cause neurodegeneration through ribosomal stalling.
“The C57BL6/J (B6J)-nmf205 mouse model has mutations in both the translation GTPase GTPBP2 and the neuronal tRNAArgUCU genes that cause neurodegeneration through ribosomal stalling (Ishimura et al., 2014, 2016).”
From Meta-Analysis of the Alzheimer’s Disease Human Brain Transcriptome and Functional Dissection in Mouse Models (2020) · cites this paper as Ishimura et al., 2016
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- Authors
- Ishimura, R., Nagy, G., Dotu, I., Chuang, J. H., & Ackerman, S. L.
- Affiliations
- Howard Hughes Medical Institute (US)
- Research Programme on Biomedical Informatics, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain
- The Jackson Laboratory for Genomic Medicine (US)
- Corresponding author
- Ackerman, Susan L
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2016-04-16
- Volume
- 5
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC4917338
- OpenAlex
- W2341404981
- Cited by
- 221
- References
- 92
- Citations by year
- 2026: 27 · 2025: 38 · 2024: 31 · 2023: 23 · 2022: 19 · 2021: 25 · 2020: 24 · 2019: 14 · 2018: 14 · 2017: 6
- FWCI
- 5.89
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion)
- Repositori digital de la UPF (Universitat Pompeu Fabra) (submittedVersion, cc-by)
- Funders
- National Institute of Neurological Disorders and Stroke (NS094637)
- Howard Hughes Medical Institute
- National Human Genome Research Institute (HG007554)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- GCN2, ribosome stalling, translation elongation, translation initiation, integrated stress response, eIF2α phosphorylation, ATF4, neurodegeneration, neuronal stress response, neuronal survival
- MeSH terms
- Animals, Mice, Inbred C57BL, Neurons, Peptide Chain Elongation, Translational, Peptide Chain Initiation, Translational, Phosphorylation, Protein Processing, Post-Translational, Ribosomes, RNA, Transfer, Arg, Eukaryotic Initiation Factor-2, Protein Serine-Threonine Kinases, GTP-Binding Proteins, Gene Expression Profiling, Activating Transcription Factor 4
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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