Abstract:
Huntington\'s disease (HD) is a fatal neurodegenerative disease associated with autophagy disorder and mitochondrial dysfunction. Here, we identified therapeutic potential of perillaldehyde (PAE), a monoterpene compound obtained from Perilla frutescens (L.) Britt., in the Caenorhabditis elegans (C. elegans) model of HD, which included lifespan extension, healthspan improvement, decrease in polyglutamine (polyQ) aggregation, and preservation of mitochondrial network. Further analyses indicated that PAE was able to induce autophagy and mitochondrial unfolded protein reaction (UPRmt) activation and positively regulated expression of associated genes. In lgg-1 RNAi C. elegans or C. elegans with UPRmt-related genes knockdown, the effects of PAE treatment on polyQ aggregation or rescue polyQ-induced toxicity were attenuated, suggesting that its neuroprotective activity depended on autophagy and UPRmt. Moreover, we found that pharmacological and genetic activation of UPRmt generally protected C. elegans from polyQ-induced cytotoxicity. Finally, PAE promoted serotonin synthesis by upregulating expression of TPH-1, and serotonin synthesis and neurosecretion were required for PAE-mediated UPRmt activation and its neuroprotective activity. In conclusion, PAE is a potential therapy for polyQ-related diseases including HD, which is dependent on autophagy and cell-non-autonomous UPRmt activation.
摘要:
亨廷顿病(HD)是一种与自噬障碍和线粒体功能障碍相关的致命性神经退行性疾病。这里,我们确定了紫苏醛(PAE)的治疗潜力,从紫苏获得的单萜化合物(L.)布里特。,在秀丽隐杆线虫(C.线虫)HD模型,其中包括延长寿命,健康的改善,聚谷氨酰胺(polyQ)聚集减少,和线粒体网络的保护。进一步的分析表明,PAE能够诱导自噬和线粒体未折叠蛋白反应(UPRmt)的激活并积极调节相关基因的表达。在lgg-1RNAiC.elegans或具有UPRmt相关基因敲低的C.elegans中,PAE处理对polyQ聚集或挽救polyQ诱导的毒性的影响减弱,提示其神经保护活性依赖于自噬和UPRmt。此外,我们发现UPRmt的药理和遗传激活通常可以保护秀丽隐杆线虫免受polyQ诱导的细胞毒性。最后,PAE通过上调TPH-1的表达来促进5-羟色胺的合成,而5-羟色胺的合成和神经分泌是PAE介导的UPRmt激活及其神经保护活性所必需的。总之,PAE是一种潜在的治疗polyQ相关疾病,包括HD,依赖于自噬和细胞非自主UPRmt激活。