Using Drosophila to investigate the glial contribution to neurodegenerative disorders

Glial cells, long considered passive bystanders of the brain, have recently been shown to be active players in normal brain physiology. While a role for glial cells in disease is beginning to be established, it remains unclear what specific role glial cells are playing in the pathogenesis of neurodegenerative disorders. In the second chapter of this dissertation, we characterized the proliferative potential of human astrocytes in a variety of neurological disorders. We observed a relatively low level of astrocytic proliferation in many of these conditions, which suggests that the major astrocytic response to these insults is most likely carried out by resident astrocytes, not newly formed ones. In the third chapter, we generated a Drosophila model of the glial tau pathology found in tauopathies, a class of Alzheimer's disease-related disorders, by overexpressing human wild-type tau in adult Drosophila glial cells. This model resulted in age-dependent degeneration of both glial and neuronal cells, and was characterized by the formation of glial fibrillary tangles similar to those found in human tauopathy brains. In the fourth chapter, we performed a forward genetic deficiency screen using the toxicity associated with the expression of human tau in Drosophila glial cells as a phenotypic readout. We identified several regions within the Drosophila genome that appear to modify this glial tau toxicity. Eventual identification of the modifying genes in these deficiencies should provide insights into the mechanism of toxicity associated with the Drosophila model of glial tauopathy. In conclusion, we investigated the contribution of glial cells to neurodegenerative disorders and neurological disease by examining human autopsy and biopsy specimens, and by creating a Drosophila model of glial tauopathy. The toxicity associated with the Drosophila model of glial tauopathy suggests that the glial tau pathology found in human tauopathies may contribute to the pathogenesis of these disorders. Taken together, these studies explore the role of glia in neurological diseases, and support the hypothesis that glial cells play an active role in the pathogenesis of neurodegenerative disorders.