Isorhynchophylline, a natural alkaloid, promotes the degradation of α-synuclein in neuronal cells via inducing autophagy
Isorhynchophylline, a natural alkaloid, promotes the degradation of α-synuclein in neuronal cells via inducing autophagy
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DOI：
10.4161/auto.8.1.18313
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发表时间：
2012-01-01
期刊：
影响因子：
13.3
通讯作者：
Li, Min
中科院分区：
文献类型：
--
作者：
Lu, Jia-Hong;Tan, Jie-Qiong;Li, Min
α-突触核蛋白（α-syn）在大脑中的积累是帕金森病的一个致病特征，也是帕金森病的一个致病因素。异钩藤碱（Isorhynchophylline，IsoRhy）是从中药钩藤（Uncariahynchophylla（Miq.）几个世纪以来，在东亚一直被用于治疗神经系统疾病。在这里，我们报告了一个新的功能，IsoRhy作为神经元自噬诱导剂。IsoRhy在不同的神经元细胞系中诱导自噬，包括N2 a、SH-SY 5 Y和PC 12细胞，以及在原代皮层神经元中。此外，IsoRhy在果蝇的脂肪体中诱导自噬。IsoRhy通过自噬-溶酶体途径促进神经元细胞中野生型、A53 T和A30 P α-syn单体、α-syn寡聚体和α-syn/synphilin-1侵袭体的清除。更重要的是，IsoRhy能够降低分化的人多巴胺能神经元中野生型和A53 T α-syn蛋白的表达水平。值得注意的是，IsoRhy诱导的自噬不依赖于mTOR途径，但依赖于Beclin 1的功能。综上所述，本研究的数据提高了羟吲哚生物碱衍生物可能作为刺激神经元细胞自噬的一种手段，从而通过减少神经元中的致病蛋白质聚集体，对神经退行性疾病如帕金森病发挥预防和治疗价值的可能性。
Accumulation of alpha-synuclein (alpha-syn) in the brain is a pathogenic feature and also a causative factor of Parkinson disease. Isorhynchophylline (IsoRhy) is a major tetracyclic oxindole alkaloid isolated from the Chinese herbal medicine Uncaria rhynchophylla (Miq.) Jacks (Gouteng in Chinese), which has been used for the treatment of neurological diseases in East Asia for centuries. Here we report a novel function of IsoRhy as a neuronal autophagy inducer. IsoRhy induced autophagy in different neuronal cell lines, including N2a, SH-SY5Y and PC12 cells, and also in primary cortical neurons. Furthermore, IsoRhy induced autophagy in the fat bodies of Drosophila. IsoRhy promoted clearance of wild-type, A53T and A30P alpha-syn monomers, alpha-syn oligomers and alpha-syn/synphilin-1 aggresomes in neuronal cells via the autophagy-lysosome pathway. More importantly, IsoRhy was able to decrease the expression levels of wild-type and A53T alpha-syn protein in differentiated human dopaminergic neurons. Notably, IsoRhy-induced autophagy was independent of the mTOR pathway but dependent on the function of Beclin 1. Taken together, data from this study raise the possibility that oxindole alkaloid derivatives may serve as a means to stimulate autophagy in neuronal cells, thereby exerting preventive and therapeutic values against neurodegenerative diseases such as Parkinson disease by reducing pathogenic protein aggregates in neurons.