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Corynoxine, a Natural Autophagy Enhancer, Promotes the Clearance of Alpha-Synuclein via Akt/mTOR Pathway

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Abstract

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 (α-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 α-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.

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Acknowledgments

The authors would like to thank Prof. David C. Rubinsztein for providing the PC12 inducible α-syn cell lines (WT and A53T) and Prof. Zhang Zhuohua for providing the Cg-GAL4 fly lines and UAS-GFP-Atg8a fly lines. This study was supported by NSFC-RGC join research grant (RGC-N_HKBU 213/11) and Innovation and Technology Support Programme research grant (ITS/274/12) from the Hong Kong Government and research grants SCM/10–11/03, IRMS/12–13/1A and FRGII/12–13/038 from Hong Kong Baptist University. The authors would also like to thank Dr. Martha Dahlen for her English editing of this manuscript.

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Authors and Affiliations

  1. School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong

    Lei-Lei Chen, Ju-Xian Song, Jia-Hong Lu, Zhen-Wei Yuan, Liang-Feng Liu, Siva Sundara Kumar Durairajan & Min Li

  2. Department of Neurology and Neurosciences, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    Jia-Hong Lu

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Fig. S1

Cory induces autophagy in N2a cells. (A) N2a cells were first treated with 5 mM 3-MA for 12h, washed with fresh DMEM medium for 3 times, and then treated with 25μM Cory for another 6h. Cell lysates were subjected to Western blotting analysis. Quantifications of LC3-II /β-actin ratio were described in (B). Data were presented as mean ± SEM of three independent experiments. (**p<0.01,Cory vs. Ctrl; ns, 3-MA vs. 3-MA+Cory, one-way ANOVA with Newman-Keuls multiple test). (JPEG 468 kb)

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Chen, LL., Song, JX., Lu, JH. et al. Corynoxine, a Natural Autophagy Enhancer, Promotes the Clearance of Alpha-Synuclein via Akt/mTOR Pathway. J Neuroimmune Pharmacol 9, 380–387 (2014). https://doi.org/10.1007/s11481-014-9528-2

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