期刊
ACS CHEMICAL BIOLOGY
卷 8, 期 7, 页码 1460-1468出版社
AMER CHEMICAL SOC
DOI: 10.1021/cb400017h
关键词
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资金
- Sid W. Richardson Foundation
- National Science Foundation [0940902]
- Division Of Graduate Education
- Direct For Education and Human Resources [0940902] Funding Source: National Science Foundation
- Div Of Chem, Bioeng, Env, & Transp Sys
- Directorate For Engineering [1254318] Funding Source: National Science Foundation
Misfolding and aggregation of alpha-synuclein (alpha-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 alpha-syn aggregates, suggesting that chaperones play a role in alpha-syn misfolding and aggregation. In fact, inhibition of chaperone activity aggravates alpha-syn toxicity, and the overexpression of chaperones, particularly 70-kDa heat shock protein (Hsp70), protects against alpha-syn-induced toxicity. In this study, we investigated the effect of carbenoxolone (CBX), a glycyrrhizic acid derivative previously reported to up regulate Hsp70, in human neuroglioma cells overexpressing alpha-syn. We report that CBX treatment lowers alpha-syn aggregation and prevents alpha-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 alpha-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 alpha-syn aggregation.
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