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Edited by Nancy M. Bonini, University of Pennsylvania, Philadelphia, PA, and approved July 11, 2016 (received for review May 25, 2016)
Significance
Heat shock protein 70 (Hsp70) is a critical protein with many protective activities inside the cell. We demonstrate that forced secretion of Hsp70 is beneficial against the extracellular protein aggregates typical of Alzheimer’s disease (AD). Engineering Hsp70 enables its interaction with the amyloid-β42 peptide, the main pathogenic agent in AD. This interaction suppresses amyloid-β toxicity in the eye, reduces cell death in brain neurons, and protects neuronal architecture and function. Interestingly, secreted Hsp70 exerts this protective activity without utilizing its refolding activity and without decreasing the levels and aggregation of amyloid-β42. These results suggest a protective mechanism mediated by direct binding to amyloid-β42, which blocks amyloid-β42 neurotoxicity. We discuss here the potential therapeutic benefits of secreted Hsp70.
Abstract
Alzheimer’s disease (AD) is the most prevalent of a large group of related proteinopathies for which there is currently no cure. Here, we used Drosophila to explore a strategy to block Aβ42 neurotoxicity through engineering of the Heat shock protein 70 (Hsp70), a chaperone that has demonstrated neuroprotective activity against several intracellular amyloids. To target its protective activity against extracellular Aβ42, we added a signal peptide to Hsp70. This secreted form of Hsp70 (secHsp70) suppresses Aβ42 neurotoxicity in adult eyes, reduces cell death, protects the structural integrity of adult neurons, alleviates locomotor dysfunction, and extends lifespan. SecHsp70 binding to Aβ42 through its holdase domain is neuroprotective, but its ATPase activity is not required in the extracellular space. Thus, the holdase activity of secHsp70 masks Aβ42 neurotoxicity by promoting the accumulation of nontoxic aggregates. Combined with other approaches, this strategy may contribute to reduce the burden of AD and other extracellular proteinopathies.
Footnotes
- ↵1To whom correspondence may be addressed. Email: pedro.ffunez{at}gmail.com or diego.rincon{at}neurology.ufl.edu.
Author contributions: P.F.-F., J.S.-G., and D.E.R.-L. designed research; P.F.-F., J.S.-G., L.d.M., Y.Z., Y.L., S.K., and D.E.R.-L. performed research; P.F.-F. and D.E.R.-L. contributed new reagents/analytic tools; P.F.-F., J.S.-G., L.d.M., Y.Z., Y.L., and D.E.R.-L. analyzed data; and P.F.-F., T.E.G., and D.E.R.-L. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1608045113/-/DCSupplemental.
secHsp70 masks Aβ42 neurotoxicity
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