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Triptolide Promotes the Clearance of α-Synuclein by Enhancing Autophagy in Neuronal Cells

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Abstract

Parkinson’s disease (PD) is an aging-associated neurodegenerative disease with a characteristic feature of α-synuclein accumulation. Point mutations (A53T, A30P) that increase the aggregation propensity of α-synuclein result in familial early onset PD. The abnormal metabolism of α-synuclein results in aberrant level changes of α-synuclein in PD. In pathological conditions, α-synuclein is degraded mainly by the autophagy-lysosome pathway. Triptolide (T10) is a monomeric compound isolated from a traditional Chinese herb. Our group demonstrated for the first time that T10 possesses potent neuroprotective properties both in vitro and in vivo PD models. In the present study, we reported T10 as a potent autophagy inducer in neuronal cells, which helped to promote the clearance of various forms of α-synuclein in neuronal cells. We transfected neuronal cells with A53T mutant (A53T) or wild-type (WT) α-synuclein plasmids and found T10 attenuated the cytotoxicity induced by pathogenic A53T α-synuclein overexpression. We observed that T10 significantly reduced both A53T and WT α-synuclein level in neuronal cell line, as well as in primary cultured cortical neurons. Excluding the changes of syntheses, secretion, and aggregation of α-synuclein, we further added autophagy inhibitor or proteasome inhibitor with T10, and we noticed that T10 promoted the clearance of α-synuclein mainly by the autophagic pathway. Lastly, we observed increased autophagy marker LC3-II expression and autophagosomes by GFP-LC3-II accumulation and ultrastructural characterization. However, the lysosome activity and cell viability were not modulated by T10. Our study revealed that T10 could induce autophagy and promote the clearance of both WT and A53T α-synuclein in neurons. These results provide evidence of T10 as a promising mean to treat PD and other neurodegenerative diseases by reducing pathogenic proteins in neurons.

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Acknowledgments

This study was supported by the Project of Construction of Innovative Teams and Teacher Career Development for Universities and Colleges under Beijing Municipality (IDHT20140514), the Projects of Beijing Municipality (TJSHG201310025006), and the Beijing Natural Science Foundation (7162019).

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Authors and Affiliations

  1. Department of Neurobiology, Capital Medical University, 10# Xitoutiao, Youanmen, Beijing, 100069, People’s Republic of China

    Guanzheng Hu, Le Wang, Mengru Liu, Yang Liu, Xia Fu, Wei Wang, Ting Zhang & Xiaomin Wang

  2. Department of Physiology, Capital Medical University, Beijing, China

    Xiaoli Gong

  3. Beijing Institute for Brain Disorders, Beijing, China

    Xiaomin Wang

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  1. Guanzheng Hu
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Correspondence to Ting Zhang or Xiaomin Wang.

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Hu, G., Gong, X., Wang, L. et al. Triptolide Promotes the Clearance of α-Synuclein by Enhancing Autophagy in Neuronal Cells. Mol Neurobiol 54, 2361–2372 (2017). https://doi.org/10.1007/s12035-016-9808-3

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  • DOI: https://doi.org/10.1007/s12035-016-9808-3

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