POLYGLUTAMINE-EXPANDED HUMAN HUNTINGTIN TRANSGENES INDUCE DEGENERATION OF DROSOPHILA PHOTORECEPTOR NEURONS

Huntington's disease (HD) is an autosomal dominant neurodegenerative d isorder. Disease alleles contain a trinucleotide repeat expansion of v ariable length, which encodes polyglutamine tracts near the amino term inus of the HD protein, huntingtin. Polyglutamine-expanded huntingtin, but not normal huntingtin, forms nuclear inclusions. We describe a Dr osophila model for HD. Amino-terminal fragments of human huntingtin co ntaining tracts of 2, 75, and 120 glutamine residues were expressed in photoreceptor neurons in the compound eye. As in human neurons, polyg lutamine-expanded huntingtin induced neuronal degeneration. The age of onset and severity of neuronal degeneration correlated with repeat le ngth, and nuclear localization of huntingtin presaged neuronal degener ation. In contrast to other cell death paradigms in Drosophila, coexpr ession of the Viral antiapoptotic protein, P35, did not rescue the cel l death phenotype induced by polyglutamine-expanded huntingtin.