Drosophila as a genetic approach to human neurodegenerative disease

Polyglutamine disease is a class of human neurodegenerative diseases charac terized by late-onset, progressive neural degeneration. The molecular mecha nism is expansion, within the coding region of the respective genes, of a C AG repeat encoding glutamine. The expanded polyglutamine domain confers dom inant 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 polyglutam ine 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 transgeni c models. Moreover, the protein shows abnormal protein aggregation in flies , similar to human disease tissue. These studies indicate that molecular me chanisms of polyglutamine-induced neurodegeneration are conserved in Drosph ila. Through these studies and additional studies to develop Ay models for other human neurodegenerative diseases, including Parkinson's disease, the power of Drosophila genetics can be brought to bear toward the molecular un derstanding and treatment of human neurodegeneration. (C) 2001 Elsevier Sci ence Ltd. All rights reserved.