title: Suppression of polyglutamine-mediated neurodegeneration in Drosophila by the molecular chaperone HSP70.
abstract: At least eight inherited human neurodegenerative diseases are caused by expansion of a polyglutamine domain within the respective proteins. This confers dominant toxicity on the proteins, leading to dysfunction and loss of neurons. Expanded polyglutamine proteins form aggregates, including nuclear inclusions (NI), within neurons, possibly due to misfolding of the proteins. NI are ubiquitinated and sequester molecular chaperone proteins and proteasome components, suggesting that disease pathogenesis includes activation of cellular stress pathways to help refold, disaggregate or degrade the mutant disease proteins. Overexpression of specific chaperone proteins reduces polyglutamine aggregation in transfected cells, but whether this alters toxicity is unknown. Using a Drosophila melanogaster model of polyglutamine disease, we show that directed expression of the molecular chaperone HSP70 suppresses polyglutamine-induced neurodegeneration in vivo. Suppression by HSP70 occurred without a visible effect on NI formation, indicating that polyglutamine toxicity can be dissociated from formation of large aggregates. Our studies indicate that HSP70 or related molecular chaperones may provide a means of treating these and other neurodegenerative diseases associated with abnormal protein conformation and toxicity.
authors.affiliation: Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Warrick
authors.forename: H Y
authors.initials: HY
authors.lastname: Chan
authors.forename: G L
authors.initials: GL
authors.lastname: Gray-Board
authors.forename: Y
authors.initials: Y
authors.lastname: Chai
authors.forename: H L
authors.initials: HL
authors.lastname: Paulson
authors.forename: N M
authors.initials: NM
authors.lastname: Bonini
mesh_terms: D000818:Animals; D000067699:Ataxin-3; D004195:Disease Models, Animal; D004331:Drosophila melanogaster / Q000235:genetics / Q000502:physiology; D005123:Eye / Q000473:pathology; D005260:Female; D015870:Gene Expression; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics* / Q000502:physiology*; D006801:Humans; D017827:Machado-Joseph Disease / Q000235:genetics / Q000628:therapy; D008297:Male; D009410:Nerve Degeneration / Q000209:etiology / Q000235:genetics* / Q000517:prevention & control*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology; D019636:Neurodegenerative Diseases / Q000628:therapy; D009687:Nuclear Proteins; D010455:Peptides / Q000235:genetics* / Q000502:physiology*; D017434:Protein Structure, Tertiary / Q000235:genetics; D012097:Repressor Proteins; D014162:Transfection
chemical_list: D018840:HSP70 Heat-Shock Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D012097:Repressor Proteins; C097188:polyglutamine; C092341:ATXN3 protein, human; D000067699:Ataxin-3