Our laboratory uses Drosophila as a model for human neurodegenerative disease. We started these studies with a polyQ disease model for the human disease spinocerebellar ataxia type 3 (SCA3). This is a movement disorder, causing ataxia. In addition to SCA3, there are a large number of other polyQ diseases, most notably Huntington’s disease. For SCA3, the normal polyQ repeat in the ataxin-3 protein becomes expanded in disease, with the protein now conferring dominant toxicity. The longer the repeat, the earlier the onset and more severe the disease. Remarkably, expression in flies of the human protein with a disease-length expanded polyQ repeat causes a disease-like phenotype in the fly: for example, expression of the pathogenic human protein in the fly eye results in severely degenerate and necrotic eyes. We have used this model in order to find modifiers of the disease that may provide the foundation for new therapeutics for the human situation. Our studies have shown that the molecular chaperones, especially Hsp70, are potent modifiers of degeneration, resulting in a fully rescued disease in the fly. More current work is focused on novel screens for additional modifiers, with focus on how they function to mitigate the degeneration. We are also interested in instability of the glutamine-encoding CAG repeat within the gene, how the neurons die in the neurodegenerative situation, and potential toxicity conferred by the RNA.
We are also studying fly models for Parkinson’s disease, a degenerative movement disorder associated with loss of dopaminergic neurons. We have characterized toxicity of one of the major proteins associated with Parkinson’s disease, alpha-synuclein. Expression of this protein in the fly causes loss of integrity of dopaminergic neurons, just like it does in humans. We are using these flies, as well as additional models for Parkinson’s disease in the fly, to study how Parkinson’s associated disease genes cause loss of neurons. We are also interested in the environmental component of Parkinson’s disease—that is, how environmental toxins integrate with genes to cause deleterious phenotypes. A number of toxins, including paraquat and rotenone are associated with Parkinson’s disease, indicating a role for toxins. Beyond these diseases, we are also developing new models for other human neurodegenerative diseases, and have a number of terrific collaborators to help us extend our findings to other model systems, and especially to the human condition. In this way, we are using genetics of the simple model organism Drosophila in order to provide new understanding, and the foundation for novel therapeutics, for human neurodegenerative disease.