HMGB1 Promotes Mitochondrial Dysfunction-Triggered Striatal Neurodegeneration via Autophagy and Apoptosis Activation.
HMGB1 Promotes Mitochondrial Dysfunction-Triggered Striatal Neurodegeneration via Autophagy and Apoptosis Activation.
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HMGB1 通过自噬和细胞凋亡激活促进线粒体功能障碍引发的纹状体神经变性
DOI：
10.1371/journal.pone.0142901
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Zhang XD
中科院分区：
文献类型：
--
作者：
Qi L;Sun X;Li FE;Zhu BS;Braun FK;Liu ZQ;Tang JL;Wu C;Xu F;Wang HH;Velasquez LA;Zhao K;Lei FR;Zhang JG;Shen YT;Zou JX;Meng HM;An GL;Yang L;Zhang XD
线粒体能量代谢障碍被认为与许多神经退行性疾病有关。线粒体抑制剂3-硝基丙酸（3-NP）在体内诱导纹状体病理模拟神经变性。既往研究表明，3-NP也可触发自噬激活和细胞凋亡。本研究以高迁移率组框1 （HMGB1）蛋白为研究对象，探讨神经退行性疾病中自噬和凋亡的机制是否与代谢损伤有关。HMGB1蛋白在氧化应激信号通路以及自噬和凋亡中起重要作用。为了阐明HMGB1在纹状体变性中的作用，我们研究了HMGB1对3-NP诱导的自噬激活和细胞死亡的影响。我们通过立体定向注射3-NP致毒大鼠纹状体，分析HMGB1、促凋亡蛋白caspase-3和磷酸c- jun氨基末端激酶（p-JNK）的表达变化。HMGB1抑制剂甘草酸显著降低了3- np诱导的p-JNK、cleaved caspase-3和自噬标志物LC3-II的升高以及SQSTM1 （p62）的降低。甘草酸还能显著抑制3- np诱导的纹状体损伤。将培养的原代纹状体神经元暴露于3-NP中可复制神经元死亡。HMGB1靶向shRNA方法对细胞的拯救表明，HMGB1在基底自噬中起重要作用。3-NP还能诱导纹状体神经元中HMGB1、p-JNK和LC3-II的表达，并且通过敲低HMGB1的shRNA可显著降低p-JNK的表达，外源增加HMGB1的表达可逆转这一作用。这些结果表明HMGB1在线粒体功能障碍引起的神经退行性变中自噬和凋亡的信号通路中都起重要作用。
Impairments in mitochondrial energy metabolism are thought to be involved in many neurodegenerative diseases. The mitochondrial inhibitor 3-nitropropionic acid (3-NP) induces striatal pathology mimicking neurodegeneration in vivo. Previous studies showed that 3-NP also triggered autophagy activation and apoptosis. In this study, we focused on the high-mobility group box 1 (HMGB1) protein, which is important in oxidative stress signaling as well as in autophagy and apoptosis, to explore whether the mechanisms of autophagy and apoptosis in neurodegenerative diseases are associated with metabolic impairment. To elucidate the role of HMGB1 in striatal degeneration, we investigated the impact of HMGB1 on autophagy activation and cell death induced by 3-NP. We intoxicated rat striata with 3-NP by stereotaxic injection and analyzed changes in expression HMGB1, proapoptotic proteins caspase-3 and phospho-c-Jun amino-terminal kinases (p-JNK). 3-NP–induced elevations in p-JNK, cleaved caspase-3, and autophagic marker LC3-II as well as reduction in SQSTM1 (p62), were significantly reduced by the HMGB1 inhibitor glycyrrhizin. Glycyrrhizin also significantly inhibited 3-NP–induced striatal damage. Neuronal death was replicated by exposing primary striatal neurons in culture to 3-NP. It was clear that HMGB1 was important for basal autophagy which was shown by rescue of cells through HMGB1 targeting shRNA approach.3-NP also induced the expression of HMGB1, p-JNK, and LC3-II in striatal neurons, and p-JNK expression was significantly reduced by shRNA knockdown of HMGB1, an effect that was reversed by exogenously increased expression of HMGB1. These results suggest that HMGB1 plays important roles in signaling for both autophagy and apoptosis in neurodegeneration induced by mitochondrial dysfunction.