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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.

Chemical Induction of Hsp70 Reduces α-Synuclein Aggregation in Neuroglioma Cells