title: Expanded polyglutamine protein forms nuclear inclusions and causes neural degeneration in Drosophila.
abstract: Spinocerebellar ataxia type 3 (SCA3/MJD) is one of at least eight human 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 expanded polyglutamine repeat led to nuclear inclusion (NI) formation and 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 degeneration. The viral antiapoptotic gene P35 mitigated polyglutamine-induced degeneration in vivo. Our results demonstrate that cellular mechanisms of human glutamine-repeat disease are conserved in invertebrates. This fly model will aid in identifying additional factors that modulate neurodegeneration.
authors.affiliation: Department of Biology, University of Pennsylvania and University of Pennsylvania Medical School, Philadelphia 19104, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Warrick
authors.forename: H L
authors.initials: HL
authors.lastname: Paulson
authors.forename: G L
authors.initials: GL
authors.lastname: Gray-Board
authors.forename: Q T
authors.initials: QT
authors.lastname: Bui
authors.forename: K H
authors.initials: KH
authors.lastname: Fischbeck
authors.forename: R N
authors.initials: RN
authors.lastname: Pittman
authors.forename: N M
authors.initials: NM
authors.lastname: Bonini
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis; D000067699:Ataxin-3; D016367:Baculoviridae; D002467:Cell Nucleus / Q000473:pathology; D004330:Drosophila; D005123:Eye / Q000473:pathology; D018390:Gene Targeting; D006801:Humans; D002479:Inclusion Bodies / Q000235:genetics*; D051034:Inhibitor of Apoptosis Proteins; D007814:Larva; D017827:Machado-Joseph Disease / Q000235:genetics / Q000473:pathology*; D009410:Nerve Degeneration / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009687:Nuclear Proteins; D009928:Organ Specificity; D010455:Peptides / Q000235:genetics; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D018911:Trinucleotide Repeats; D014764:Viral Proteins / Q000235:genetics / Q000502:physiology
chemical_list: D051034:Inhibitor of Apoptosis Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D014764:Viral Proteins; C086430:inhibitor of apoptosis, Nucleopolyhedrovirus; C097188:polyglutamine; C092341:ATXN3 protein, human; D000067699:Ataxin-3