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.
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.
|de la Monte, Suzanne M; Tong, Ming; Wands, Jack R (2018) The 20-Year Voyage Aboard the Journal of Alzheimer's Disease: Docking at 'Type 3 Diabetes', Environmental/Exposure Factors, Pathogenic Mechanisms, and Potential Treatments. J Alzheimers Dis 62:1381-1390|
|Donahue, John E; Yakirevich, Evgeny; Zhong, Shan et al. (2018) Primary Spinal Epidural CIC-DUX4 Undifferentiated Sarcoma in a Child. Pediatr Dev Pathol 21:411-417|
|Mandelbaum, David E; Arsenault, Amanda; Stonestreet, Barbara S et al. (2018) Neuroinflammation-Related Encephalopathy in an Infant Born Preterm Following Exposure to Maternal Diabetic Ketoacidosis. J Pediatr 197:286-291.e2|
|de la Monte, Suzanne M; Kay, Jared; Yalcin, Emine B et al. (2018) Imaging mass spectrometry of frontal white matter lipid changes in human alcoholics. Alcohol 67:51-63|
|Tong, Ming; Gonzalez-Navarrete, Howard; Kirchberg, Tyler et al. (2017) Ethanol-Induced White Matter Atrophy Is Associated with Impaired Expression of Aspartyl-Asparaginyl-?-Hydroxylase (ASPH) and Notch Signaling in an Experimental Rat Model. J Drug Alcohol Res 6:|
|Tong, Ming; Leão, Raiane; Vimbela, Gina V et al. (2017) Altered temporal lobe white matter lipid ion profiles in an experimental model of sporadic Alzheimer's disease. Mol Cell Neurosci 82:23-34|
|Tai, Marlene; Piskorski, Anna; Kao, Jennifer C W et al. (2017) Placental Morphology in Fetal Alcohol Spectrum Disorders. Alcohol Alcohol 52:138-144|
|Lee, Han-Kyu; Kwon, Bumsup; Lemere, Cynthia A et al. (2017) mTORC2 (Rictor) in Alzheimer's Disease and Reversal of Amyloid-? Expression-Induced Insulin Resistance and Toxicity in Rat Primary Cortical Neurons. J Alzheimers Dis 56:1015-1036|
|Yalcin, Emine B; McLean, Tory; Tong, Ming et al. (2017) Progressive white matter atrophy with altered lipid profiles is partially reversed by short-term abstinence in an experimental model of alcohol-related neurodegeneration. Alcohol 65:51-62|
|de la Monte, Suzanne M; Tong, Ming; Schiano, Irio et al. (2017) Improved Brain Insulin/IGF Signaling and Reduced Neuroinflammation with T3D-959 in an Experimental Model of Sporadic Alzheimer's Disease. J Alzheimers Dis 55:849-864|
Showing the most recent 10 out of 99 publications