Research proposed in this application seeks to utilize Drosophila melanogaster to determine the role of the microtubule-associated protein (MAP) tau in the pathogenesis of human tauopathies. The tau protein has been implicated in at least 20 neurodegenerative diseases collectively referred to as tauopathies, including Alzheimer?s disease, frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17), and progressive supranuclear palsy. Normally, tau is a highly soluble protein whose proposed function is to promote axonal outgrowth and stability in the central nervous system (CNS) through the binding of microtubules. A pathological hallmark of the clinically heterogeneous tauopathies is the presence of insoluble, fllamentous tau aggregates in neuronal and glial cells. The molecular mechanisms by which these cytoplasmic tau inclusions facilitate the neurodegenerative process have yet to be elucidated. Specifically, questions as to whether neuronal loss occurs due to a toxic gain-of-function from the presence of aggregated tau or due to a loss-of-function of the normal activity of the tau protein, or both still remain unanswered. To address these issues, we have begun to develop a model of human tauopathy in the invertebrate D. melanogaster, a molecularly, developmentally and genetically well-characterized organism. Our approach has employed the GAL4-UAS expression system to ectopically express wild-type and disease-associated mutant forms of human tau in an attempt to recapitulate the tau-associated pathology in the fly. Additionally, we have cloned the Drosophila tau homologue and are in the process of a mutagenesis screen to identify loss-of-function alleles in the tau locus. Using these complementary approaches, we hope to exploit the power of the fly model system to determine the cellular role of tau in maintaining neuronal integrity and how disruption of that function results in neuronal loss.