Suppression of polyglutamine-mediated neurodegeneration in Drosophila by the molecular chaperone HSP70

At least eight inherited human neurodegenerative diseases are caused by exp ansion of a polyglutamine domain within the respective proteins(1,2). This confers dominant toxicity on the proteins, leading to dysfunction and loss of neurons. Expanded polyglutamine proteins form aggregates, including nucl ear inclusions (NI), within neurons, possibly due to misfolding of the prot eins(3-5). MI are ubiquitinated and sequester molecular chaperone proteins and proteasome components(6-9), suggesting that disease pathogenesis includ es activation of cellular stress pathways to help refold, disaggregate or d egrade the mutant disease proteins. Overexpression of specific chaperone pr oteins reduces polyglutamine aggregation in transfected cells(7-9), but whe ther this alters toxicity is unknown. Using a Drosophila melanogaster model of polyglutamine disease(10), we show that directed expression of the mole cular chaperone HSP70 suppresses polyglutamine-induced neurodegeneration in vivo. Suppression by HSP70 occurred without a visible effect on NI formati on, indicating that polyglutamine toxicity can be dissociated from formatio n of large aggregates. Our studies indicate that HSP70 or related molecular chaperones may provide a means of treating these and other neurodegenerati ve diseases associated with abnormal protein conformation and toxicity.