Ethanol inhibition of aspartyl-asparaginyl-β-hydroxylase in fetal alcohol spectrum disorder: Potential link to the impairments in central nervous system neuronal migration

Abstract

Fetal alcohol spectrum disorder (FASD) is caused by prenatal exposure to alcohol and associated with hypoplasia and impaired neuronal migration in the cerebellum. Neuronal survival and motility are stimulated by insulin and insulin-like growth factor (IGF), whose signaling pathways are major targets of ethanol neurotoxicity. To better understand the mechanisms of ethanol-impaired neuronal migration during development, we examined the effects of chronic gestational exposure to ethanol on aspartyl (asparaginyl)-β-hydroxylase (AAH) expression, because AAH is regulated by insulin/IGF and mediates neuronal motility. Pregnant Long—Evans rats were pair-fed isocaloric liquid diets containing 0, 8, 18, 26, or 37% ethanol by caloric content from gestation day 6 through delivery. Cerebella harvested from postnatal day 1 pups were used to examine AAH expression in tissue, and neuronal motility in Boyden chamber assays. We also used cerebellar neuron cultures to examine the effects of ethanol on insulin/IGF—stimulated AAH expression, and assess the role of GSK-3β—mediated phosphorylation on AAH protein levels. Chronic gestational exposure to ethanol caused dose-dependent impairments in neuronal migration and corresponding reductions in AAH protein expression in developing cerebella. In addition, prenatal ethanol exposure inhibited insulin and IGF-I—stimulated directional motility in isolated cerebellar granule neurons. Ethanol-treated neuronal cultures (50 mM × 96 h) also had reduced levels of AAH protein. Mechanistically, we showed that AAH protein could be phosphorylated on Ser residues by GSK-3β, and that chemical inhibition of GSK-3β and/or global Caspases increases AAH protein in both control- and ethanol-exposed cells. Ethanol-impaired neuronal migration in FASD is associated with reduced AAH expression. Because ethanol increases the activities of both GSK-3β and Caspases, the inhibitory effect of ethanol on neuronal migration could be mediated by increased GSK-3β phosphorylation and Caspase degradation of AAH protein.

Aspartate β-hydroxylase expression promotes a malignant pancreatic cellular phenotype

“…Transcriptional regulation of ASPH is provided by tripartite signaling pathways: insulin (IN) and insulin like growth factor 1 (IGF1)/insulin-receptor substrate type 1 (IRS1)/MAPK/ERK, IN/IGF1/IRS1/PI3K/AKT, and WNT/β-Catenin [22, 23]. Post-transcriptional regulation of ASPH is mediated by phosphorylation of GSK3β-related motifs located in the N-terminal region of the molecule [24]. The present study attempts to address several questions central to the function of ASPH in PC.…”

Potential Role of Phosphorylation as a Regulator of Aspartyl-(asparaginyl)-β-hydroxylase: Relevance to Infiltrative Spread of Human Hepatocellular Carcinoma

“…In addition, AAH is regulated by glycogen synthase kinase-3β (GSK-3β), protein kinase A (PKA), protein kinase C (PKC), and casein kinase 2 (CK2), each of which could potentially phosphorylate AAH protein [26,31,32,33]. Thus far, most of the work done on this topic has concerned the role of GSK-3β.…”

A Potential Administration-time Dependent Effect of Bevacizumab in Improving Overall Survival and Increasing Metastasis in Metastatic Colorectal Cancer

“…Consequently, gestational ethanol exposure impaired transformation of maternal decidual arteries such that the degree of impairment correlated with timing and duration of the insult, and severity of IUGR. The paradoxical response of glycogen cells may have been due to ethanol-inhibition of trophoblast cell motility and invasion [4,5,7]. Impaired motility of glycogen cells into the mesometrial triangle could account for their observed accumulation in the junctional zone.…”

“…In addition, the adverse effects of ethanol were found to be mediated by inhibition of Aspartyl-Asparaginylβ-Hydroxylase (AAH) [5]. AAH is aninsulin/IGF-responsive gene, whose hydroxylase activity regulates cell motility and invasion [6,7]. Furthermore, gestational exposure to ethanol reduced the number of secondary trophoblast giant cells [4] and altered trophoblast subtype-specific gene expression [3].…”