Alexander disease: mechanisms, modifiers, and therapeutics

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DESCRIPTION: Alexander disease is a rare and typically fatal neurodegenerative disease of childhood that results from heterozygous mutations in the gene encoding the type III intermediate filament protein GFAP. The pathological signature of the disorder is the Rosenthal fiber, a cytoplasmic inclusion containing intermediate filaments and small heat shock proteins that accumulates in astrocytes throughout the CNS. Prior investigations by our group have let to the acceptance of GFAP mutations as the cause for nearly all cases of Alexander disease, and the rapid translation of this information to clinical practice as the standard for diagnosis. However, the mechanisms by which GFAP mutations cause astrocyte dysfunction and disease remain unclear. The goals of this Program Project are to develop novel model systems of human astrocytes, investigate the impact of mutant GFAP and GFAP excess in astrocytes on neuronal development, viability, and function, and study the pathways by which mis-folded proteins are cleared from the brain. In addition, we will identify and characterize genetic modifiers of disease phenotype and test potential strategies for treatment. Our studies span genetic, biochemical, cellular, physiological, and morphological approaches to these questions, and include model systems ranging from invertebrate through human. The Program will link four laboratories, one using human induced pluripotent stem cells, one using Drosophila, and two using mouse models. An administrative core will coordinate financial reporting, monitor IACUC approvals, and support communication between the groups as well as with the internal and external advisory committees. The Program will promote a focused effort on the role of GFAP in disease, by fostering sharing of reagents, animals, and results among the four labs, through cross-fertilization of ideas, and by regular communication and meetings among laboratory members. These studies promise novel insights into the consequences of GFAP toxicity and the role of astrocytes in brain function and disease. Our hope is that such studies will ultimately lea to strategies for mitigating the devastating effects of astrocyte dysfunction.