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

Nature Genetics volume 23, pages 425–428 (1999)Cite this article

Abstract

At 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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Figure 1: Drosophila HSP70 localizes to nuclear inclusions.
Figure 2: HSP70 suppresses polyglutamine-induced neurodegeneration in vivo.
Figure 3: HSP70 slows progressive degeneration of the nervous system.
Figure 4: NI formation in flies expressing polyglutamine protein and HSPA1L.
Figure 5: A dominant-negative form of a constitutively expressed cytoplasmic fly HSP70 enhances polyglutamine disease.

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Acknowledgements

We thank A. Cashmore and L. Lillien for critical reading of the manuscript. This research was funded in part by grants from the R.J. Carver Charitable Trust, faculty start-up funding from the University of Iowa Howard Hughes Medical Institute Resources Program (H.L.P.), the Wills Foundation (J.M.W.), the Wellcome Trust (H.Y.E.C.), the HDSA Coalition for the Cure, Hereditary Disease Foundation, Alzheimer's Foundation and the David and Lucile Packard Foundation (N.M.B.).

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Authors and Affiliations

  1. Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania, USA

    John M. Warrick, H.Y. Edwin Chan, Gladys L. Gray-Board & Nancy M. Bonini

  2. Department of Neurology, University of Iowa College of Medicine, Iowa City, Iowa, USA

    Yaohui Chai & Henry L. Paulson

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  1. John M. Warrick
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  6. Nancy M. Bonini
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Correspondence to Nancy M. Bonini.

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Warrick, J., Chan, H., Gray-Board, G. et al. Suppression of polyglutamine-mediated neurodegeneration in Drosophila by the molecular chaperone HSP70. Nat Genet 23, 425–428 (1999). https://doi.org/10.1038/70532

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