Expanded polyglutamine protein forms nuclear inclusions and causes neural degeneration in Drosophila.
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.
Warrick
J M
JM
Department of Biology, University of Pennsylvania and University of Pennsylvania Medical School, Philadelphia 19104, USA.
Paulson
H L
HL
Gray-Board
G L
GL
Bui
Q T
QT
Fischbeck
K H
KH
Pittman
R N
RN
Bonini
N M
NM
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
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