Abstract
Background:
Branched-chain keto acid dehydrogenase kinase (BDK) deficiency reduces branched chain amino acids and causes epilepsy with autistic features.
Results:
Loss of general control nonderepressible 2 (GCN2) in BDK
−/−
mice results in a fatal leukodystrophy.
Conclusion:
GCN2 is essential for protecting glial cells during amino acid deficiency.
Significance:
This study contributes novel information toward understanding the heterogeneous basis of white matter diseases.
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
Tnf
α 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.