EXPANDED POLYGLUTAMINE PROTEIN FORMS NUCLEAR INCLUSIONS AND CAUSES NEURAL DEGENERATION IN DROSOPHILA

Spinocerebellar ataxia type 3 (SCA3/MJD) is one of at least eight huma n neurodegenerative diseases caused by glutamine-repeat expansion. We have recreated glutamine-repeat disease in Drosophila using a segment of the SCA3/MJD protein. Targeted expression of the protein with an ex panded polyglutamine repeat led to nuclear inclusion (NI) formation an d late-onset cell degeneration. Differential sensitivity to the mutant transgene was observed among different cell types, with neurons being particularly susceptible; NI formation alone was not sufficient for d egeneration. The viral antiapoptotic gene P35 mitigated polyglutamine- induced degeneration in vivo. Our results demonstrate that cellular me chanisms of human glutamine-repeat disease are conserved in invertebra tes. This fly model will aid in identifying additional factors that mo dulate neurodegeneration.