title: Chemical induction of Hsp70 reduces α-synuclein aggregation in neuroglioma cells.
abstract: Misfolding and aggregation of α-synuclein (α-syn) is associated with the development of a number of neurodegenerative diseases including Parkinson's disease (PD). Analyses of post mortem tissues revealed the presence of molecular chaperones within α-syn aggregates, suggesting that chaperones play a role in α-syn misfolding and aggregation. In fact, inhibition of chaperone activity aggravates α-syn toxicity, and the overexpression of chaperones, particularly 70-kDa heat shock protein (Hsp70), protects against α-syn-induced toxicity. In this study, we investigated the effect of carbenoxolone (CBX), a glycyrrhizic acid derivative previously reported to upregulate Hsp70, in human neuroglioma cells overexpressing α-syn. We report that CBX treatment lowers α-syn aggregation and prevents α-syn-induced cytotoxicity. We demonstrate further that Hsp70 induction by CBX arises from activation of heat shock factor 1 (HSF1). The Hsp70 inhibitor MAL3-101 and the Hsp70 enhancer 115-7c led to an increase or decrease in α-syn aggregation, respectively, in agreement with these findings. In summary, this study provides a proof-of-principle demonstration that chemical modulation of the Hsp70 machine is a promising strategy to prevent α-syn aggregation.
authors.affiliation: Departments of †Chemical and Biomolecular Engineering, ∥Bioengineering, and ⊥Biochemistry and Cell Biology, Rice University , Houston, Texas 77005, United States.
authors.forename: Kiri
authors.initials: K
authors.lastname: Kilpatrick
authors.forename: Jose Andres
authors.initials: JA
authors.lastname: Novoa
authors.forename: Tommy
authors.initials: T
authors.lastname: Hancock
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Guerriero
authors.forename: Peter
authors.initials: P
authors.lastname: Wipf
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Brodsky
authors.forename: Laura
authors.initials: L
authors.lastname: Segatori
mesh_terms: D000897:Anti-Ulcer Agents / Q000494:pharmacology; D002229:Carbenoxolone / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D018840:HSP70 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D015394:Molecular Structure; D011485:Protein Binding / Q000187:drug effects; D017510:Protein Folding; D014407:Tumor Cells, Cultured; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D000897:Anti-Ulcer Agents; D018840:HSP70 Heat-Shock Proteins; D051844:alpha-Synuclein; D002229:Carbenoxolone