title: Combined pharmacological induction of Hsp70 suppresses prion protein neurotoxicity in Drosophila.
abstract: Prion diseases are rare and aggressive neurodegenerative disorders caused by the accumulation of misfolded, toxic conformations of the prion protein (PrP). Therapeutic strategies directed at reducing the levels of PrP offer the best chance of delaying or halting disease progression. The challenge, though, is to define pharmacologic targets that result in reduced PrP levels. We previously reported that expression of wild type hamster PrP in flies induces progressive locomotor dysfunction and accumulation of pathogenic PrP conformations, while co-expression of human Hsp70 delayed these changes. To validate the therapeutic potential of Hsp70, we treated flies with drugs known to induce Hsp70 expression, including the Hsp90 inhibitor 17-DMAG and the glucocorticoid dexamethasone. Although the individual treatment with these compounds produced no significant benefits, their combination significantly increased the level of inducible Hsp70, decreased the level of total PrP, reduced the accumulation of pathogenic PrP conformers, and improved locomotor activity. Thus, the combined action of two pharmacological activators of Hsp70 with distinct targets results in sustained high levels of inducible Hsp70 with improved behavioral output. These findings can have important therapeutic applications for the devastating prion diseases and other related proteinopathies.
authors: Department of Neurology, McKnight Brain Institute, University of Florida, Gainesville, Florida, United States of America.
authors: Yan
authors: Y
authors: Zhang
authors: Department of Molecular, Cellular and developmental Neurobiology, Instituto Cajal, Madrid, Spain.
authors: Sergio
authors: S
authors: Casas-Tinto
authors: Department of Neurology, McKnight Brain Institute, University of Florida, Gainesville, Florida, United States of America ; Department of Neurosciences, Genetics Institute, and Center for Translational Research on Neurodegenerative Diseases, Gainesville, Florida, United States of America.
authors: Diego E
authors: DE
authors: Rincon-Limas
authors: Department of Neurology, McKnight Brain Institute, University of Florida, Gainesville, Florida, United States of America ; Department of Neurosciences, Genetics Institute, and Center for Translational Research on Neurodegenerative Diseases, Gainesville, Florida, United States of America ; Center for Movement Disorders and Neurorestoration, Gainesville, Florida, United States of America.
authors: Pedro
authors: P
authors: Fernandez-Funez
mesh_terms: D000818:Animals; D016227:Benzoquinones / Q000737:chemistry; D006224:Cricetinae; D003907:Dexamethasone / Q000737:chemistry; D004195:Disease Models, Animal; D018450:Disease Progression; D004330:Drosophila / Q000378:metabolism*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D047029:Lactams, Macrocyclic / Q000737:chemistry; D009069:Movement Disorders / Q000188:drug therapy / Q000378:metabolism*; D017096:Prion Diseases / Q000188:drug therapy / Q000378:metabolism*; D011328:Prions; D011487:Protein Conformation; D017510:Protein Folding
chemical_list: D016227:Benzoquinones; D018840:HSP70 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D011328:Prions; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin; D003907:Dexamethasone; C001277:geldanamycin