General control nonderepressible 2 (GCN2) kinase protects oligodendrocytes and white matter during branched-chain amino acid deficiency in mice.
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.
['She|Pengxiang|P|', 'Bunpo|Piyawan|P|', 'Cundiff|Judy K|JK|', 'Wek|Ronald C|RC|', 'Harris|Robert A|RA|', 'Anthony|Tracy G|TG|']
D000818:Animals D002374:Catalase D002540:Cerebral Cortex D015852:Eukaryotic Initiation Factor-2 D005260:Female D005786:Gene Expression Regulation D006801:Humans D056784:Leukoencephalopathies D008297:Male D008375:Maple Syrup Urine Disease D051379:Mice D018345:Mice, Knockout D004676:Myelin Basic Protein D009836:Oligodendroglia D018384:Oxidative Stress D011494:Protein Kinases D017346:Protein Serine-Threonine Kinases D013482:Superoxide Dismutase D014409:Tumor Necrosis Factor-alpha
Amino Acid Epilepsy Brain Myelin Leukodystrophy Endoplasmic Reticulum Stress Gene Knock-out Glia Translation Initiation Factors