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.