title: A genetic model for human polyglutamine-repeat disease in Drosophila melanogaster.
abstract: To apply genetics to the problem of human polyglutamine-repeat disease, we recreated polyglutamine-repeat disease in Drosophila melanogaster. To do this, we expressed forms of the human gene encoding spinocerebellar ataxia type 3, also called Machado-Joseph disease (SCA-3/MJD). This gene is responsible for the most common form of human ataxia worldwide. Expression of a normal form of the MJD protein with 27 polyglutamines (MJDtr-Q27) had no phenotype. However, expression of a form of the protein with an expanded run of 78 glutamines (MJDtr-Q78) caused late onset progressive degeneration. In addition, the MJDtr-Q78 formed abnormal protein aggregates, or nuclear inclusions (NIs), whereas the control protein was cytoplasmic. These data indicate that the mechanisms of human polyglutamine-repeat disease are conserved to Drosophila. We are currently using this model to address potential mechanisms by which the mutant disease protein causes neural degeneration, as well as to define genes that can prevent polyglutamine-induced degeneration. By applying the power of Drosophila genetics to the problem of human polyglutamine-induced neural degeneration, we hope to identify ways to prevent and treat these diseases in humans.
authors.affiliation: Department of Biology, University of Pennsylvania, Philadelphia 19104-6018, USA. nbonin@sas.upenn.edu
authors.forename: N M
authors.initials: NM
authors.lastname: Bonini
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D000067699:Ataxin-3; D004331:Drosophila melanogaster / Q000235:genetics*; D006801:Humans; D017827:Machado-Joseph Disease / Q000235:genetics*; D008957:Models, Genetic; D009410:Nerve Degeneration / Q000235:genetics / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics*; D009687:Nuclear Proteins; D010455:Peptides / Q000235:genetics*; D020449:Repetitive Sequences, Amino Acid; D012097:Repressor Proteins
chemical_list: D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D012097:Repressor Proteins; C097188:polyglutamine; C092341:ATXN3 protein, human; D000067699:Ataxin-3