The Bonini laboratory focuses on applying the extraordinary power of a very simple model organism — the fruit fly Drosophila — to the complex problem of human neurodegenerative disease. Many human neurodegenerative diseases, like the dementia-causing Alzheimer’s disease and the motor neuron disease ALS, are associated with the abnormal accumulation of key proteins in which mutations are found in inherited situations; these same proteins accumulate in sporadic disease as well. Although disease mechanisms have classically been studied in systems like the mouse or in cell culture, instead we developed the much simpler system Drosophila for this end. Drosophila shares genes and pathways with humans, including basic aspects of brain structure. Our studies illustrate how remarkable insight can be gleaned from Drosophila by recreating the features of the human disease in the fly, and then employing the range of genetic approaches available to uncover surprising molecular mechanisms. Importantly, the genetics of the animal also holds promise to reveal the foundation for unsuspected and new therapeutic approaches. In this way, this very simple system can contribute important insight toward an understanding of the basic biology of human disease, as well as outline approaches to intervention.
Nancy Bonini is the Florence R.C. Murray Professor of Biology at the University of Pennsylvania and a Howard Hughes Medical Institute Investigator. Her laboratory focuses on using Drosophila melanogaster as a tool to define genes important for human brain disease. A class of human neurodegenerative diseases involves expansion of a polyglutamine repeat within the various disease proteins. This polyglutamine expansion results in a dominant, toxic property of the disease protein, leading to neural degeneration. Huntington’s disease is of this class. We have recreated this class of human neurodegenerative disease in Drosophila by expressing in flies one of these human disease proteins with an expanded polyglutamine run. Whereas expression of the protein with a normal polyglutamine repeat has no effect, expression of the protein with an expanded polyglutamine repeat results in late onset, progressive degeneration in the nervous system. This indicates that the molecular mechanisms of human polyglutamine disease are conserved in Drosophila. Hence, we are now using Drosophila to define genes involved in the mechanisms and progression of polyglutamine disease, to identify suppressor mutations that can prevent or delay brain degeneration, and to extend these studies to additional diseases, like Parkinson’s disease and other motor neuron diseases. The Bonini lab is also expanding into neural injury and aging models in Drosophila by analyzing the nervous system with age. They hope that these studies will lead to insight into neural decline with aging, providing an approach for new treatments.