Journal
ACTA NEUROPATHOLOGICA
Volume 116, Issue 3, Pages 303-315Publisher
SPRINGER
DOI: 10.1007/s00401-008-0377-z
Keywords
aspartyl (asparaginyl)-beta-hydroxylase; fetal alcohol spectrum disorders; Caspase; neuronal migration; insulin; central nervous system; glycogen synthase kinase 3 beta
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Funding
- NIAAA NIH HHS [R37 AA002666, AA-02169, R01 AA002666, AA-16126, K24 AA016126, R56 AA011431, R01 AA011431, AA12908, R37 AA011431, R01 AA012908, AA02666, AA-11431] Funding Source: Medline
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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)-beta-hydroxylase (AAH) is a mediator of neuronal motility, and stimulated by insulin and IGF activation of PI3 kinase-Akt, or inhibition of GSK-3 beta. Since ethanol inhibits PI3 Kinase-Akt and increases GSK-3 beta activity in brain, we examined the effects of ethanol and GSK-3 beta on AAH expression and directional motility in neuronal cells. Control and ethanol-exposed (100 mM x 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-3 beta 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-3 beta; (2) high levels of GSK-3 beta activity decreased AAH protein; (3) inhibition of GSK-3 beta 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-3 beta 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-3 beta 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-3 beta and Caspase activation, e.g. IGF resistance and increased oxidative stress.
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