title: General control nonderepressible 2 (GCN2) kinase protects oligodendrocytes and white matter during branched-chain amino acid deficiency in mice.
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.
authors.affiliation: From the Department of Nutritional Sciences, Rutgers, State University of New Jersey, New Brunswick, New Jersey 08901.
authors.forename: Pengxiang
authors.initials: P
authors.lastname: She
authors.forename: Piyawan
authors.initials: P
authors.lastname: Bunpo
authors.forename: Judy K
authors.initials: JK
authors.lastname: Cundiff
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Wek
authors.forename: Robert A
authors.initials: RA
authors.lastname: Harris
authors.forename: Tracy G
authors.initials: TG
authors.lastname: Anthony
mesh_terms: D000818:Animals; D002374:Catalase / Q000096:biosynthesis / Q000235:genetics; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D056784:Leukoencephalopathies / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008297:Male; D008375:Maple Syrup Urine Disease / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D004676:Myelin Basic Protein / Q000096:biosynthesis / Q000235:genetics; D009836:Oligodendroglia / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000235:genetics; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000096:biosynthesis / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics; D000099156:Superoxide Dismutase 2
chemical_list: D002374:Catalase; D015852:Eukaryotic Initiation Factor-2; D004676:Myelin Basic Protein; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D013482:Superoxide Dismutase; D014409:Tumor Necrosis Factor-alpha; D000099156:Superoxide Dismutase 2; C070634:Eif2ak4 protein, mouse; C035627:(3-methyl-2-oxobutanoate dehydrogenase (lipoamide)) kinase
keywords: Amino Acid; Brain; Endoplasmic Reticulum Stress; Epilepsy; Gene Knock-out; Glia; Leukodystrophy; Myelin; Translation Initiation Factors
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