The molecular mechanisms underlying neurodegeneration in human disorders like Alzheimer's disease and Parkinson's disease remain 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 postmitotic 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 Gerhig's disease), Alexander'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 alpha-synuclein, and progressive locomotor dysfunction. We are now using the genetic and molecular tools available in Drosophila to investigate cellular pathways required for the pathogenesis of Parkinson's disease.

We haven taken similar approaches to modeling Alzheimer's disease, amyotrophic lateral sclerosis, Alexander's disease and polyglutamine disorders in Drosophila. Genetic screens have been performed or are underway in these models as well to define the cellular pathways mediating neurodegeneration. Candidate proteins defined in the Drosophila models are being investigated in mammalian systems, including human disease, to evaluate the role of the proteins in the pathogenesis of human neurodegenerative disorders.