Most work in the area of brain disease research focuses on neuronal mechanisms of toxicity. However, gliacomprise the most abundant class of cells in the nervous system and subserve important roles inneurotransmitter uptake, ammonia detoxification and other critical processes. Although astrocytes appear tobe in a primary position to affect brain function in pathological conditions, little is known about the functionalrole of these cells in disease states. Mutations in the gene encoding the astrocyte-specific intermediatefilament, glial fibrillary acidic protein (GFAP), cause Alexander disease, a typically childhood disorder thatmanifests with seizures and severe white matter pathology. Dysmyelination is accompanied by theformation of GFAP-rich inclusions in astrocytes termed Rosenthal fibers. The presence of GFAP in theseaggregates and the observation that overexpression of GFAP in mouse astrocytes produces a severeneurological syndrome and Rosenthal fiber formation has led to the hypothesis that Alexander disease isproduced by a dominant gain of function mechanism, perhaps related to abnormal aggregation of GFAP. Totest this hypothesis and create a1 model of Alexander disease, we have expressed normal and mutantversions of GFAP in Drosophila. We find that overexpression of GFAP in the Drosophila retina and glialeads to formation of numerous GFAP-containing, Rosenthal-fiber like inclusion bodies. Inclusion bodyformation is accompanied by degeneration in the retina. In this pilot proposal we will optimize the retinaldegeneration phenotype for use in genetic screening experiments. We will then perform a limited preliminaryscreen to evaluate the utility of the retinal degeneration phenotype and to identify genetic modifiers of GFAPtoxicity.Relevance: Although nonneuronal (or glial) cells are important in normal brain function, their role in diseasestates is largely unknown. We have created a model a rare, devastating disorder called Alexander disease,to explore the role of glia in neurological diseases. A prominent feature of Alexander disease, and of our fruitfly model of the disoder, is the formation of insoluble protein aggregates. More common disorders likeAlzheimer's disease and Parkinson's disease also have abnormal protein aggregates. Thus, our work mayhave important implications for understanding and therapy of these diseases as well.
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