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.
|Original language||English (US)|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|State||Published - Aug 30 2016|
Bibliographical noteFunding Information:
We thank Shailaja Emani for technical assistance, Nancy Bonini (University of Pennsylvania) for the human HSPA1L construct and flies, Mary Konsolaki (Rutgers University) for the GMR-A?42(4?) flies, Ben-Zion Shilo (Weizmann Institute for Science) for the secGFP flies, Bradley Hyman (Massachusetts General Hospital) for the HEK293 cells/split-luciferase A?42, Amit Singh (University of Dayton) for the optimized TUNEL protocol, Hermann Steller (Rockefeller University) for the anti-Hsc3 antibody, the Bloomington Drosophila Stock Center (NIH P40OD018537) for fly strains, and the Developmental Studies Hybridoma Bank for antibodies. This work was supported by NIH Grants DP2 OD002721-01 (to P.F.-F.) and R21NS081356 (to D.E.R.-L.) and a McKnight Brain Institute Research Development Award (to P.F.-F. and D.E.R.-L.).
- Engineered chaperones