Studies performed during the previous grant period established that chronic gestational exposure to ethanol impairs neuronal migration in the developing brain, and that this effect of ethanol is associated with reduced expression and function of a critical target gene, aspartyl- aparaginyl-?-hydroxylase (AAH), which has a demonstrated role in cell motility. We identified 3 mechanisms of ethanol-impaired AAH expression and function: 1) ethanol exposure causes insulin and insulin-like growth factor (IGF) resistance, inhibiting downstream signaling through PI3K-Akt, Erk MAPK, and Cdk-5 pathways that regulate AAH mRNA;2) ethanol increases GSK-3? activity, and high levels of GSK-3? cause increased AAH phosphorylation, possibly rendering AAH more susceptible to degradation by Caspases;and 3) ethanol inhibits AAH's catalytic activity which is required for AAH to promote cell motility. We hypothesize that AAH promotes neuronal motility by hydroxylating Notch, which then undergoes cleavage and translocation to the nucleus where it regulates gene expression. Our overarching goal is to demonstrate mechanisms of ethanol-impaired neuronal migration, focusing on the role of GSK- 3?-mediated phosphorylation and attendant inhibition of AAH protein expression, catalytic activity, and motility.
Specific Aim 1 is to characterize the effects of GSK-3?-mediated phosphorylation of AAH on AAH protein expression, synthesis, degradation, and catalytic activity.
Specific Aim 2 will examine the role of increased GSK-3? activity and phosphorylation of AAH as a mediator of ethanol-impaired AAH protein expression, AAH hydroxylase activity, and neuronal motility.
Specific Aim 3 is to evaluate the effects of GSK-3? phosphorylation of AAH on Notch signaling, and link those effects to the impairments in downstream gene expression and CNS neuronal migration that occur in FASD. Moreover, since preliminary studies showed that AAH can physically interact with Notch (which may be important for hydroxylation), we will examine the effects of GSK-3?-phosphorylation of AAH on the physical interactions between AAH and Notch, Notch cleavage, Notch translocation to the nucleus, and downstream stimulation of the Notch-regulated target genes, e.g. Hes-1, p21/Waf-1, or presenilin-1. We plan to utilize graded in vivo and in vitro ethanol exposure models to mimic real life conditions. We expect these investigations to generate new information about the mechanisms by which ethanol inhibits AAH expression and function, and reveal the consequences with respect to the impairments in CNS neuronal migration that occur in FASD.

Public Health Relevance

In the USA, alcohol abuse during pregnancy is the most common preventable cause of congenital cognitive-motor deficits that range from mental retardation to attention deficit hyperactivity disorders. Alcohol-induced cognitive-motor impairments are associated with major disturbances in neuronal survival, growth, motility, and plasticity in the central nervous system (CNS). Our research focuses on how ethanol inhibits expression and function of aspartyl-aparaginyl-?-hydroxylase (AAH), an important molecule/enzyme that regulates neuronal migration during development. Our research is novel and could lead to new strategies for early detection and treatment of congenital CNS abnormalities caused by in utero ethanol exposure in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AA011431-16
Application #
8517513
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Murray, Gary
Project Start
1996-09-30
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
16
Fiscal Year
2013
Total Cost
$292,258
Indirect Cost
$103,094
Name
Rhode Island Hospital
Department
Type
DUNS #
075710996
City
Providence
State
RI
Country
United States
Zip Code
02903
de la Monte, Suzanne M; Tong, Ming (2014) Brain metabolic dysfunction at the core of Alzheimer's disease. Biochem Pharmacol 88:548-59
Tong, Ming; Longato, Lisa; Ramirez, Teresa et al. (2014) Therapeutic reversal of chronic alcohol-related steatohepatitis with the ceramide inhibitor myriocin. Int J Exp Pathol 95:49-63
de la Monte, Suzanne M (2014) Relationships between diabetes and cognitive impairment. Endocrinol Metab Clin North Am 43:245-67
de la Monte, Suzanne M; Kril, Jillian J (2014) Human alcohol-related neuropathology. Acta Neuropathol 127:71-90
Derdak, Zoltan; Lang, Charles H; Villegas, Kristine A et al. (2011) Activation of p53 enhances apoptosis and insulin resistance in a rat model of alcoholic liver disease. J Hepatol 54:164-72
Gundogan, Fusun; Elwood, Gwen; Mark, Princess et al. (2010) Ethanol-induced oxidative stress and mitochondrial dysfunction in rat placenta: relevance to pregnancy loss. Alcohol Clin Exp Res 34:415-23
Brennan-Krohn, Thea; Salloway, Stephen; Correia, Stephen et al. (2010) Glial Vascular Degeneration in CADASIL. J Alzheimers Dis :
de la Monte, Suzanne M; Tong, Ming; Nguyen, VanAnh et al. (2010) Ceramide-mediated insulin resistance and impairment of cognitive-motor functions. J Alzheimers Dis 21:967-84
Luu, Martin; Sabo, Edmond; de la Monte, Suzanne M et al. (2009) Prognostic value of aspartyl (asparaginyl)-beta-hydroxylase/humbug expression in non-small cell lung carcinoma. Hum Pathol 40:639-44
Tong, Ming; Dong, Matthew; de la Monte, Suzanne M (2009) Brain insulin-like growth factor and neurotrophin resistance in Parkinson's disease and dementia with Lewy bodies: potential role of manganese neurotoxicity. J Alzheimers Dis 16:585-99

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