A genetic model for human polyglutamine-repeat disease in Drosophila melanogaster

To apply genetics to the problem of human polyglutamine-repeat disease, we recreated polyglutamine-repeat disease in Drosophila melanogaster. To do th is, we expressed forms of the human gene encoding spinocerebellar ataxia ty pe 3, also called Machado-Joseph disease (SCA-3/MJD). This gene is responsi ble for the most common form of human ataxia worldwide. Expression of a nor mal form of the MJD protein with 27 polyglutamines (MJDtr-Q27) had no pheno type. However, expression of a form of the protein with an expanded run of 78 glutamines (MJDtr-Q78) caused late onset progressive degeneration. In ad dition, the MJDtr-Q78 formed abnormal protein aggregates, or nuclear inclus ions (NIs), whereas the control protein was cytoplasmic. These data indicat e that the mechanisms of human polyglutamine-repeat disease are conserved t o Drosophila. We are currently using this model to address potential mechan isms by which the mutant disease protein causes neural degeneration, as wel l as to define genes that can prevent polyglutamine-induced degeneration. B y applying the power of Drosophila genetics to the problem of human polyglu tamine-induced neural degeneration, we hope to identify ways to prevent and treat these diseases in humans.