Chemical induction of Hsp70 reduces α-synuclein aggregation in neuroglioma cells.
Chemical induction of Hsp70 reduces α-synuclein aggregation in neuroglioma cells.
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DOI：
10.1021/cb400017h
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发表时间：
2013-07-19
影响因子：
4
通讯作者：
Segatori L
中科院分区：
文献类型：
--
作者：
Kilpatrick K;Novoa JA;Hancock T;Guerriero CJ;Wipf P;Brodsky JL;Segatori L
α-突触核蛋白 (α-syn) 的错误折叠和聚集与包括帕金森病 (PD) 在内的许多神经退行性疾病的发生有关。对死后组织的分析揭示了 α-syn 聚集体中分子伴侣的存在，表明分子伴侣在 α-syn 错误折叠和聚集中发挥作用。事实上，抑制分子伴侣活性会加剧 α-syn 毒性，而分子伴侣，特别是 70-kDa 热休克蛋白 (Hsp70) 的过度表达，可以防止 α-syn 诱导的毒性。在这项研究中，我们研究了甘草酸衍生物 (CBX) 在过度表达 α-syn 的人类神经胶质瘤细胞中的作用，CBX 是一种先前报道可上调 Hsp70 的甘草酸衍生物。我们报告说，CBX 治疗可降低 α-syn 聚集并防止 α-syn 诱导的细胞毒性。我们进一步证明 CBX 诱导 Hsp70 是由热休克因子 1 (HSF1) 的激活引起的。 Hsp70 抑制剂 MAL3-101 和 Hsp70 增强剂 115-7c 分别导致 α-syn 聚集增加或减少，与这些发现一致。总之，这项研究提供了原理证明，证明 Hsp70 机器的化学调节是防止 α-syn 聚集的一种有前景的策略。
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.