Corynoxine, a Natural Autophagy Enhancer, Promotes the Clearance of Alpha-Synuclein via Akt/mTOR Pathway
Corynoxine, a Natural Autophagy Enhancer, Promotes the Clearance of Alpha-Synuclein via Akt/mTOR Pathway
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DOI：
10.1007/s11481-014-9528-2
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发表时间：
2014-06-01
影响因子：
6.2
通讯作者：
Li, Min
中科院分区：
文献类型：
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作者：
Chen, Lei-Lei;Song, Ju-Xian;Li, Min
帕金森病（PD）是第二常见的神经退行性疾病，其特征在于大脑黑质区域中多巴胺能神经元中蛋白质聚集体（即路易体）的积累。α-突触核蛋白（α-syn）是PD患者路易体的主要成分，自噬-溶酶体系统的损伤与其蓄积有关。在我们以前的研究中，我们鉴定了一个氧化吲哚生物碱Corynoxine B（Cory B），从钩藤（Uncaria rhynchophylla（Miq.）Jacks（Goteng in Chinese），作为Beclin-1依赖的自噬诱导剂。在这项工作中，我们表明，科里，科里B的对映体，也诱导自噬在不同的神经元细胞系，包括N2 a和SHSY-5 Y细胞，这是增加的溶酶体酶组织蛋白酶D。在体内，Cory促进果蝇脂肪体中自噬体的形成。通过诱导自噬，Cory促进可诱导PC 12细胞中野生型和A53 T α-syn的清除。有趣的是，与其对映异构体Cory B不同，Cory通过Akt/mTOR途径诱导自噬，如磷酸-Akt、磷酸-mTOR和磷酸-p70 S6激酶水平的降低所证明的。总之，我们的研究结果为开发Cory作为一种新的自噬增强剂提供了实验证据，该自噬增强剂可能在PD的预防或治疗中具有潜在的应用。
Parkinson's disease (PD) is the second most common neurodegenerative disorder characterized by the accumulation of protein aggregates (namely Lewy bodies) in dopaminergic neurons in the substantia nigra region of the brain. Alpha-synuclein (alpha-syn) is the major component of Lewy bodies in PD patients, and impairment of the autophagy-lysosomal system has been linked to its accumulation. In our previous study, we identified an oxindole alkaloid Corynoxine B (Cory B), isolated from Uncaria rhynchophylla (Miq.) Jacks (Gouteng in Chinese), as a Beclin-1-dependent autophagy inducer. In this work, we show that Cory, an enantiomer of Cory B, also induces autophagy in different neuronal cell lines, including N2a and SHSY-5Y cells, which is paralleled with increased lysosomal enzyme cathepsin D. In vivo, Cory promotes the formation of autophagosomes in the fat bodies of Drosophila. By inducing autophagy, Cory promotes the clearance of wild-type and A53T alpha-syn in inducible PC12 cells. Interestingly, different from its enantiomer Cory B, Cory induces autophagy through the Akt/mTOR pathway as evidenced by the reduction in the levels of phospho-Akt, phospho-mTOR and phospho-p70 S6 Kinase. Collectively, our findings provide experimental evidence for developing Cory as a new autophagy enhancer from Chinese herbal medicine, which may have potential application in the prevention or treatment of PD.