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
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.