title: Holdase activity of secreted Hsp70 masks amyloid-β42 neurotoxicity in Drosophila.
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.
authors.affiliation: Department of Neurology, McKnight Brain Institute, University of Florida, Gainesville, FL 32611; Department of Neuroscience, Center for Translational Research on Neurodegenerative Diseases, University of Florida, Gainesville, FL 32611; Genetics Institute, University of Florida, Gainesville, FL 32611 pedro.ffunez@gmail.com diego.rincon@neurology.ufl.edu.
authors.forename: Pedro
authors.initials: P
authors.lastname: Fernandez-Funez
authors.affiliation: Department of Neurology, McKnight Brain Institute, University of Florida, Gainesville, FL 32611;
authors.forename: Jonatan
authors.initials: J
authors.lastname: Sanchez-Garcia
authors.affiliation: Department of Neurology, McKnight Brain Institute, University of Florida, Gainesville, FL 32611;
authors.forename: Lorena
authors.initials: L
authors.lastname: de Mena
authors.affiliation: Department of Neurology, McKnight Brain Institute, University of Florida, Gainesville, FL 32611;
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Neuroscience, Center for Translational Research on Neurodegenerative Diseases, University of Florida, Gainesville, FL 32611;
authors.forename: Yona
authors.initials: Y
authors.lastname: Levites
authors.affiliation: Department of Neurology, McKnight Brain Institute, University of Florida, Gainesville, FL 32611;
authors.forename: Swati
authors.initials: S
authors.lastname: Khare
authors.affiliation: Department of Neurology, McKnight Brain Institute, University of Florida, Gainesville, FL 32611; Department of Neuroscience, Center for Translational Research on Neurodegenerative Diseases, University of Florida, Gainesville, FL 32611;
authors.forename: Todd E
authors.initials: TE
authors.lastname: Golde
authors.affiliation: Department of Neurology, McKnight Brain Institute, University of Florida, Gainesville, FL 32611; Department of Neuroscience, Center for Translational Research on Neurodegenerative Diseases, University of Florida, Gainesville, FL 32611; Genetics Institute, University of Florida, Gainesville, FL 32611 pedro.ffunez@gmail.com diego.rincon@neurology.ufl.edu.
authors.forename: Diego E
authors.initials: DE
authors.lastname: Rincon-Limas
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D030801:Animals, Genetically Modified; D004195:Disease Models, Animal; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism*; D005123:Eye / Q000378:metabolism; D005260:Female; D005818:Genetic Engineering / Q000379:methods; D057809:HEK293 Cells; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008136:Longevity / Q000235:genetics; D008297:Male; D000068079:Motor Disorders / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D009474:Neurons / Q000378:metabolism; D000066829:Neuroprotection / Q000235:genetics; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding
chemical_list: D016229:Amyloid beta-Peptides; D018840:HSP70 Heat-Shock Proteins; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)
keywords: Drosophila; Hsp70; amyloid-β; engineered chaperones; neuroprotections