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

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• 作者：Kiri Kilpatrick ; Jose Andres Novoa ; Tommy Hancock ; Christopher J. Guerriero ; Peter Wipf ; Jeffrey L. Brodsky ; Laura Segatori
• 刊名：ACS Chemical Biology
• 出版年：2013
• 出版时间：July 19, 2013
• 年：2013
• 卷：8
• 期：7
• 页码：1460-1468
• 全文大小：504K
• 年卷期：v.8,no.7(July 19, 2013)
• ISSN：1554-8937

文摘

Misfolding and aggregation of 伪-synuclein (伪-syn) is associated with the development of a number of neurodegenerative diseases including Parkinson鈥檚 disease (PD). Analyses of post mortem tissues revealed the presence of molecular chaperones within 伪-syn aggregates, suggesting that chaperones play a role in 伪-syn misfolding and aggregation. In fact, inhibition of chaperone activity aggravates 伪-syn toxicity, and the overexpression of chaperones, particularly 70-kDa heat shock protein (Hsp70), protects against 伪-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 伪-syn. We report that CBX treatment lowers 伪-syn aggregation and prevents 伪-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 伪-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 伪-syn aggregation.