Alexander disease (AxD) is a homogeneous disorder from a genetic perspective, with over 95% of patients accounted by mutations in a single gene, GFAP, and no other genes currently associated with the disease. Despite this genetic homogeneity, patients exhibit a wide range of clinical phenotypes, with ages of onset ranging from fetal through the seventh decade of life, differing distributions of lesions, varying degrees of leukodystrophy, and mild to severe courses. Using cell culture and animal models we have found that a key factor in pathogenesis is the subsequent accumulation of GFAP protein above a toxic threshold. The accumulation of GFAP results from a combination of both increased synthesis and decreased degradation. By engineering mouse strains that are exact genetic mimics of the human disease, and placing the GFAP mutations on different genetic backgrounds, we have discovered marked differences between strains in the levels of GFAP accumulation, and corresponding measures of disease severity, that follow from expression of mutant GFAP. These data strongly suggest the presence of one or more genetic modifiers that influence the induction of GFAP in response to injury. In addition, results from our collaborators studying Drosophila models of AxD implicate nitric oxide as a key mediator of glial-neuronal toxicity, and one that is amenable to both genetic and pharmacological investigation. Recent experiments from our lab also demonstrate deficits in adult neurogenesis, a new phenotype that has not previously been studied in AxD.
In Specific Aim 1 we will perform expression QTL analysis to identify genetic modifiers that regulate GFAP accumulation in AxD, with a focus on hippocampus and corpus callosum.
In Specific Aim 2 we will test the hypothesis that one particular gene, encoding inducible nitric oxide synthase (iNOS), is a key modifier of the overall AxD phenotype in mice.
In Specific Aim 3 we will determine whether the deficit in adult neurogenesis results from the expression of mutant GFAP in neural stem cells or mature astrocytes. These studies promise novel insights into the genetic influences on disease severity in AxD, will test the validity of a target that may be amenable to therapeutic interventions, and will identify the cellular origin of the newly identified deficit in adult neurogenesis.
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