General control nonderepressible 2 (GCN2) kinase protects oligodendrocytes and white matter during branched-chain amino acid deficiency in mice

Pengxiang She, Piyawan Bunpo, Judy K. Cundiff, Ronald Wek, Robert Harris, Tracy G. Anthony

Research output: Contribution to journalArticle

5 Citations (Scopus)

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 GBDKbrains. 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.

Original languageEnglish
Pages (from-to)31250-31260
Number of pages11
JournalJournal of Biological Chemistry
Volume288
Issue number43
DOIs
StatePublished - Oct 25 2013

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Branched Chain Amino Acids
Oligodendroglia
Brain
Phosphotransferases
Amino Acids
3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)
Eukaryotic Initiation Factor-2
Messenger RNA
Phosphorylation
Myelin Basic Protein
White Matter
Anorexia
Tremor
Cell death
Ataxia
Myelin Sheath
Genetic Markers
Neuroglia
Astrocytes
Epilepsy

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

General control nonderepressible 2 (GCN2) kinase protects oligodendrocytes and white matter during branched-chain amino acid deficiency in mice. / She, Pengxiang; Bunpo, Piyawan; Cundiff, Judy K.; Wek, Ronald; Harris, Robert; Anthony, Tracy G.

In: Journal of Biological Chemistry, Vol. 288, No. 43, 25.10.2013, p. 31250-31260.

Research output: Contribution to journalArticle

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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 GBDKbrains. 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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