Acta Neuropathologica

, Volume 116, Issue 3, pp 303–315

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

  • Jade J. Carter
  • Ming Tong
  • Elizabeth Silbermann
  • Stephanie A. Lahousse
  • Fei Fei Ding
  • Lisa Longato
  • Nitin Roper
  • Jack R. Wands
  • Suzanne M. de la Monte
Original Paper

DOI: 10.1007/s00401-008-0377-z

Cite this article as:
Carter, J.J., Tong, M., Silbermann, E. et al. Acta Neuropathol (2008) 116: 303. doi:10.1007/s00401-008-0377-z

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.

Keywords

Aspartyl (asparaginyl)-β-hydroxylaseFetal alcohol spectrum disordersCaspaseNeuronal migrationInsulinCentral nervous systemGlycogen synthase kinase 3β

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Jade J. Carter
    • 1
  • Ming Tong
    • 1
  • Elizabeth Silbermann
    • 1
  • Stephanie A. Lahousse
    • 1
  • Fei Fei Ding
    • 1
  • Lisa Longato
    • 1
  • Nitin Roper
    • 1
  • Jack R. Wands
    • 1
  • Suzanne M. de la Monte
    • 1
  1. 1.Departments of Medicine and Pathology, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, and the Pathobiology Graduate ProgramBrown UniversityProvidenceUSA