Nature Genetics
23, 425 - 428 (1999)
doi:10.1038/70532
Suppression of polyglutamine-mediated neurodegeneration in Drosophila by the molecular chaperone HSP70John M. Warrick1, H.Y. Edwin Chan1, Gladys L. Gray-Board1, Yaohui Chai2, Henry L. Paulson2
& Nancy M. Bonini11
Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania, USA. 2
Department of Neurology, University of Iowa College of Medicine, Iowa City, Iowa, USA.
Correspondence should be addressed to Nancy M. Bonini nbonini@sas.upenn.eduAt least eight inherited human neurodegenerative diseases are caused by expansion of a polyglutamine domain within the respective proteins1,
2. 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 proteins3,
4,
5. NI are ubiquitinated and sequester molecular chaperone proteins and proteasome components6,
7,
8,
9, 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 cells7,
8,
9, but whether this alters toxicity is unknown. Using a Drosophila melanogaster model of polyglutamine disease10, 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.
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