Research

research

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.