Ethanol impaired neuronal migration is associated with reduced aspartyl-asparaginyl-β-hydroxylase expression

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Abstract
Cerebellar hypoplasia in fetal alcohol spectrum disorders (FASD) is associated with inhibition of insulin and insulin-like growth factor (IGF) signaling in the brain. Aspartyl (asparaginyl)-β-hydroxylase (AAH) is a mediator of neuronal motility, and stimulated by insulin and IGF activation of PI3 kinase-Akt, or inhibition of GSK-3β. Since ethanol inhibits PI3 Kinase-Akt and increases GSK-3β activity in brain, we examined the effects of ethanol and GSK-3β on AAH expression and directional motility in neuronal cells. Control and ethanol-exposed (100 mM × 48 h) human PNET2 cerebellar neuronal cells were stimulated with IGF-1 and used to measure AAH expression and directional motility. Molecular and biochemical approaches were used to characterize GSK-3β regulation of AAH and neuronal motility. Ethanol reduced IGF-1 stimulated AAH protein expression and directional motility without inhibiting AAH’s mRNA. Further analysis revealed that: (1) AAH protein could be phosphorylated by GSK-3β; (2) high levels of GSK-3β activity decreased AAH protein; (3) inhibition of GSK-3β and/or global Caspases increased AAH protein; (4) AAH protein was relatively more phosphorylated in ethanol-treated compared with control cells; and (5) chemical inhibition of GSK-3β and/or global Caspases partially rescued ethanol-impaired AAH protein expression and motility. Ethanol-impaired neuronal migration is associated with reduced IGF-I stimulated AAH protein expression. This effect may be mediated by increased GSK-3β phosphorylation and Caspase degradation of AAH. Therapeutic strategies to rectify CNS developmental abnormalities in FASD should target factors underlying the ethanol-associated increases in GSK-3β and Caspase activation, e.g. IGF resistance and increased oxidative stress.

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