Alexander Disease: Cellular and Molecular Mechanisms, Project 2: Drosophila Model of Alexander Disease
Alexander disease, in its most common form, is a fatal leukodystrophy typically affecting young children for which the pathologic hallmark is the widespread deposition of Rosenthal fibers in subpial, perivascular, and periventricular astrocytes. Nearly all Alexander patients, including those with juvenile or adult-onset forms of the disease, carry heterozygous mutations within the coding region of the gene for GFAP. These mutations predict expression of abnormal GFAP proteins, which act in a dominant gain-of-function fashion. Alexander disease is the first known primary disorder of astrocytes, and as such it provides unique opportunities for furthering our understanding of the role that astrocyte dysfunction plays in disease, and for discovering potential pathways that are amenable to therapy. Our hope is by focusing on this disorder we will generate new knowledge and strategies that are useful in other diseases that share similar pathogenic pathways involving protein aggregation and astrocyte dysfunction.
The specific goals of Project 2 (PI, M.B. Feany) are the development and utilization of a Drosophila model of Alexander disease. In particular, we are currently carrying out comprehensive forward genetic screens aimed at identifying, in an unbiased fashion, the mechanisms by which GFAP accumulation is harmful to glial cells, and then promotes non-cell autonomous dysfunction and death of neurons. Preliminary results of these genetic screens are very promising because pathways identified as causative for nervous system dysfunction and neuronal and glial pathology in Drosophila are also dysregulated in mouse models of Alexander disease.