The molecular mechanisms underlying neurodegeneration in human disorders like Alzheimer’s disease and Parkinson’s disease remain largely mysterious, in part because genetic analysis in patients and vertebrate models is laborious. Disease models in simpler organisms, like Drosophila, harness the power of genetics to define cellular pathways underlying the specific destruction of post mitotic neurons in neurodegenerative disorders.

In our laboratory we have created fruit fly models of several human diseases, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (Lou Gehrig’s disease), and spinocerebellar ataxia type 1 (a disease produced by expanded polyglutamine repeats). Mutations in the alpha-synuclein gene cause familial Parkinson’s disease, and alpha-synuclein protein accumulates in intraneuronal inclusion bodies in both familial and nonfamilial Parkinson’s disease. By expressing normal and mutant human alpha-synuclein in flies, we have recreated key features of the human disorder: dopaminergic neurodegeneration, intracytoplasmic neuronal inclusion bodies containing a-synuclein, and progressive locomotor dysfunction. We have taken similar approaches to modeling Alzheimer’s disease, amyotrophic lateral sclerosis, and polyglutamine disorders in Drosophila. Genetic screens have been performed in these models to define the cellular pathways mediating neurodegeneration. When our genetic screens and follow up mechanistic analysis in Drosophila identify new pathways that are attractive candidates for targeting by drugs in patients, we validate these pathways in higher animal models, including rats and mice. We also use our fly models to perform drug screens directly in the intact, behaving animal.