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), Huntington's disease, and spinocerebellar ataxia type 1. Mutations in the a-synuclein gene cause familial Parkinson's disease. a-synuclein protein accumulates in intraneuronal inclusion bodies in both familial and nonfamilial Parkinson's disease. By expressing normal and mutant human a-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 are now using the genetic tools available in Drosophila to identify novel genes and proteins required for the pathogenesis of Parkinson's disease.

We have taken a similar approach to modeling Alzheimer's disease. The microtubule binding protein tau is deposited in neurofibrillary tangles in Alzheimer's disease and related disorders (often termed “tauopathies”). Familial forms of dementia with neurofibrillary tangles are caused by mutation in the tau gene. To model Alzheimer's disease and other tauopathies, we expressed wild-type and mutant versions of the tau in Drosophila. Expression of human tau in flies truncates life span and produces an age-dependent neurodegeneration.

We also have created Drosophila models of amyotrophic lateral sclerosis and polyglutamine disorders. Genetic screens are underway in all our models 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.