This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Depression and alcoholism are increasingly understood as debilitating and oftentimes fatal disorders, and co-occur more commonly than expected by chance. The molecular mechanisms contributing to observed neuronal and glial cell loss in both major depressive disorder and alcoholism remain unclear. Recent studies have focused on the apoptotic role of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a traditional glycolytic enzyme. Several groups have reported that GAPDH translocates into the cell nucleus when cells are stressed. Our preliminary data show that cell stressors or ethanol increase the expression of GAPDH in brain-derived cell lines and also increase the binding of GAPDH with early growth response-1 (Egr-1), resulting in nuclear translocation of the GAPDH/Egr-1 complex. Treatment of brain-derived cell lines with both cell stressors and ethanol increases GAPDH expression and the interaction of GAPDH/Egr-1 more than that of treatment with cell stressors or ethanol alone. Our pilot data also demonstrate that when compared to normal control subjects, GAPDH levels are more elevated in the prefrontal cortex of subjects with co-morbid depression plus alcoholism than in subjects with either depression or alcoholism alone. In the current application, we propose a novel GAPDHmediated neuronal stress pathway that may involve GAPDH binding to Egr-1. Once inside the nucleus, the GAPDHEgr-1 complex separates, Egr-1 targets the monoamine oxidase B (MAO B) gene, thus increasing the expression of MAO B. MAO B then enzymatically degrades a number of neurotransmitters, producing toxic reactive oxygen (H2O2) and resulting in neuronal cell stress which promotes cell death or apoptosis. We hypothesize that the GAPDH-Egr-1-MAO-B-mediated neuronal stress pathway contributes to the pathogenesis of depression and alcoholism and is more evident in co-morbid depression and alcoholism than in either depression or alcoholism alone. We further hypothesize that the inhibition of the GAPDH-Egr-1-MAO-Bmediated neuronal stress pathway will protect brain cells from harmful stress- and ethanol-induced effects.
Our Specific Aims are: (1) to characterize the components active in the GAPDH-Egr-1-MAO-B -mediated neuronal stress pathway by measuring the apoptotic marker (fragmented DNA) and the levels of Egr-1 and MAO B (the downstream targets of GAPDH) in the prefrontal cortex from stressed or ethanol-treated rats as compared to untreated controls;(2) to examine the expression of apoptotic markers (fragmented DNA), GAPDH and its downstream targets in postmortem brain tissue from depressed alcoholic subjects as compared to depressed subjects, alcohol-dependent subjects and normal control subjects;and (3) to disrupt the GAPDH-Egr-1-MAO-B -mediated neuronal stress pathway (using the siRNA) to test the hypothesis that inhibition of GAPDH will reduce the harmful effects of cell stressors and ethanol. These studies are relevant to other CPN projects, because excessive glutamate signaling (Subproject 2) has been reported to trigger the GAPDH-mediated neuronal cell death cascade. The GAPDH-Egr-1-MAO-B pathway may contribute to this death cascade which causes brain cell loss in major depression (Subproject 1). Furthermore, GAPDH affects the genetic regulation of MAO, a key enzyme in degradation of serotonin. Thus, elucidating the GAPDH-Egr- 1-MAO-B -mediated neuronal stress/cell death pathway may provide new insights into serotonin system dysfunction (Subprojects 3 and 4), and might lead to novel therapeutic strategies for co-morbid depression and alcoholism.
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