GSK 3beta, a Mediator of Ethanol Neurotoxicity

Ethanol is a neuroteratogen and alcohol consumption during pregnancy causes Fetal Alcohol Spectrum Disorders (FASD). FASD are currently the leading cause of mental retardation in North America. The most devastating effect of developmental exposure to ethanol is the loss of CNS neurons which underlie many behavioral deficits observed in FASD. We demonstrated that ethanol caused both oxidative stress and endoplasmic reticulum (ER) stress in the developing brain. We showed that ethanol induced the expression of monocyte chemoattractant protein-1 (MCP-1) and a specific ER stress-inducible protein, mesencephalic astrocyte-derived neurotrophic factor (MANF). Our studies suggested that both MCP-1 and its receptor CCR2 as well as MANF were involved in ethanol-induced ER stress and neurodegeneration. The central hypothesis for this proposal is that ethanol-induced neurodegeneration in the developing brain is mediated by the interplay of oxidative stress and ER stress. Three corollary hypotheses will be tested: 1) ethanol-mediated oxidative stress causes an early neurodegeneration; the second phase of neurodegeneration is mainly mediated by ethanol-induced ER stress or a combined action of both oxidative stress and ER stress; 2) the oxidative stress-induced neurodegeneration is mainly regulated by the mitochondrial intrinsic apoptotic pathway; while the ER stress-induced neurodegeneration is mediated by the GSK3â/calpain/caspase7/12 pathway; 3) activation of MCP-1/CCR2-mediated signaling potentiates ethanol-induced ER stress and promotes an ER stress-initiated apoptotic program in neurons; contrarily, MANF is a neuroprotective protein which alleviates ethanol-induced ER stress and neurodegeneration. We propose three specific aims to test these hypotheses using both in vitro and in vivo models. Specific Aim 1 will test the hypothesis that ethanol-induced neurodegeneration is caused by the interplay of oxidative stress and ER stress in vitro. Specific Aim 2 will determine the role of MCP-1/CCR2 signaling and MANF in ethanol-induced ER stress and neurodegeneration in the developing brain. Specific Aim 3 will determine whether simultaneous inhibition of oxidative stress and ER stress offer maximal protection and improved behavioral deficits in mice. As a unit, this proposal will systematically investigate the interplay of oxidative stress and ER stress and assess their contribution to ethanol-induced neurodegeneration. This study will therefore not only provide novel insight into the mechanisms of ethanol-induced damage to the developing CNS but also identify specific targets for developing effective therapeutic strategies.