Chemical induction of Hsp70 reduces ?-synuclein aggregation in neuroglioma cells.

ABSTRACT: Misfolding and aggregation of ?-synuclein (?-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 ?-syn aggregates, suggesting that chaperones play a role in ?-syn misfolding and aggregation. In fact, inhibition of chaperone activity aggravates ?-syn toxicity, and the overexpression of chaperones, particularly 70-kDa heat shock protein (Hsp70), protects against ?-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 ?-syn. We report that CBX treatment lowers ?-syn aggregation and prevents ?-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 ?-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 ?-syn aggregation.

SUBMITTER: Kilpatrick K 

PROVIDER: S-EPMC4532326 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature