ArticleThe Journal of biological chemistry2013
General control nonderepressible 2 (GCN2) kinase protects oligodendrocytes and white matter during branched-chain amino acid deficiency in mice.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
14 citing papers in PubMed, 20 citations in OpenAlex.
- A metabolic basis for motor deficits in mice lacking BCKDK.The Journal of nutritional biochemistry · 2026Article
- Branched chain amino acid sufficiency is necessary for proper luteinizing hormone response and testosterone synthesis.Reproductive biology · 2026Article
- GCN2-Mediated eIF2α Phosphorylation Is Required for Central Nervous System Remyelination.International journal of molecular sciences · 2025Article
- Dynamic Interplay between Social Brain Development and Nutrient Intake in Young Children.Nutrients · 2023Article
- Surviving and Adapting to Stress: Translational Control and the Integrated Stress Response.Antioxidants & redox signaling · 2023Review
- MARS1 mutations linked to familial trigeminal neuralgia via the integrated stress response.The journal of headache and pain · 2023Article
- GATOR2 complex-mediated amino acid signaling regulates brain myelination.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- The integrated stress response: From mechanism to disease.Science (New York, N.Y.) · 2020Review
- GCN2 is essential for CD8Cancer immunology, immunotherapy : CII · 2020Article
- Nutritional Regulation of Gene Expression: Carbohydrate-, Fat- and Amino Acid-Dependent Modulation of Transcriptional Activity.International journal of molecular sciences · 2019Review
- Nutrient Sensing and Redox Balance: GCN2 as a New Integrator in Aging.Oxidative medicine and cellular longevity · 2019Review
- Interactions between human microbiome, diet, enteric viruses and immune system: Novel insights from gnotobiotic pig research.Drug discovery today. Disease models · 2018Review
- Muscle-specific deletion of BDK amplifies loss of myofibrillar protein during protein undernutrition.Scientific reports · 2017Article
- Homeostatic responses to amino acid insufficiency.Animal nutrition (Zhongguo xu mu shou yi xue hui) · 2015Review
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
Branched-chain amino acid (BCAA) catabolism is regulated by branched-chain α-keto acid dehydrogenase, an enzyme complex that is inhibited when phosphorylated by its kinase (BDK). Loss of BDK function in mice and humans causes BCAA deficiency and epilepsy with autistic features. In response to amino acid deficiency, phosphorylation of eukaryotic initiation factor 2α (eIF2∼P) by general control nonderepressible 2 (GCN2) activates the amino acid stress response. We hypothesized that GCN2 functions to protect the brain during chronic BCAA deficiency. To test this idea, we generated mice lacking both Gcn2 and Bdk (GBDK) and examined the development of progeny. GBDK mice appeared normal at birth, but they soon stopped growing, developed severe ataxia, tremor, and anorexia, and died by postnatal day 15. BCAA levels in brain were diminished in both Bdk(-/-) and GBDK pups. Brains from Bdk(-/-) pups exhibited robust eIF2∼P and amino acid stress response induction, whereas these responses were absent in GBDK mouse brains. Instead, myelin deficiency and diminished expression of myelin basic protein were noted in GBDK brains. Genetic markers of oligodendrocytes and astrocytes were also reduced in GBDK brains in association with apoptotic cell death in white matter regions of the brain. GBDK brains further demonstrated reduced Sod2 and Cat mRNA and increased Tnfα mRNA expression. The data are consistent with the idea that loss of GCN2 during BCAA deficiency compromises glial cell defenses to oxidative and inflammatory stress. We conclude that GCN2 protects the brain from developing a lethal leukodystrophy in response to amino acid deficiencies.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.