Drosophila as a genetic approach to human neurodegenerative disease.

Polyglutamine disease is a class of human neurodegenerative diseases characterized by late-onset, progressive neural degeneration. The molecular mechanism is expansion, within the coding region of the respective genes, of a CAG repeat encoding glutamine. The expanded polyglutamine domain confers dominant toxicity on the disease protein, leading to neuronal dysfunction and degeneration. In order to develop Drosophila as a model system to approach and study such human diseases, a human gene encoding an expanded polyglutamine protein was introduced into the fly. Expression of this protein with a pathogenic polyglutamine domain causes late-onset, progressive degeneration of cells in the fly, as it does in humans with disease and mouse transgenic models. Moreover, the protein shows abnormal protein aggregation in flies, similar to human disease tissue. These studies indicate that molecular mechanisms of polyglutamine-induced neurodegeneration are conserved in Drosophila. Through these studies and additional studies to develop fly models for other human neurodegenerative diseases, including Parkinson's disease, the power of Drosophila genetics can be brought to bear toward the molecular understanding and treatment of human neurodegeneration.