title: Triptolide Promotes the Clearance of α-Synuclein by Enhancing Autophagy in Neuronal Cells.
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.
authors.affiliation: Department of Neurobiology, Capital Medical University, 10# Xitoutiao, Youanmen, Beijing, 100069, People's Republic of China.
authors.forename: Guanzheng
authors.initials: G
authors.lastname: Hu
authors.affiliation: Department of Physiology, Capital Medical University, Beijing, China.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Gong
authors.affiliation: Department of Neurobiology, Capital Medical University, 10# Xitoutiao, Youanmen, Beijing, 100069, People's Republic of China.
authors.forename: Le
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Neurobiology, Capital Medical University, 10# Xitoutiao, Youanmen, Beijing, 100069, People's Republic of China.
authors.forename: Mengru
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Neurobiology, Capital Medical University, 10# Xitoutiao, Youanmen, Beijing, 100069, People's Republic of China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Neurobiology, Capital Medical University, 10# Xitoutiao, Youanmen, Beijing, 100069, People's Republic of China.
authors.forename: Xia
authors.initials: X
authors.lastname: Fu
authors.affiliation: Department of Neurobiology, Capital Medical University, 10# Xitoutiao, Youanmen, Beijing, 100069, People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Neurobiology, Capital Medical University, 10# Xitoutiao, Youanmen, Beijing, 100069, People's Republic of China. zhang.t@ccmu.edu.cn.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Neurobiology, Capital Medical University, 10# Xitoutiao, Youanmen, Beijing, 100069, People's Republic of China. xmwang@ccmu.edu.cn.|Beijing Institute for Brain Disorders, Beijing, China. xmwang@ccmu.edu.cn.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Wang
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects* / Q000502:physiology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004224:Diterpenes / Q000494:pharmacology*; D004852:Epoxy Compounds / Q000494:pharmacology; D005260:Female; D008247:Lysosomes / Q000187:drug effects* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D019636:Neurodegenerative Diseases / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010616:Phenanthrenes / Q000494:pharmacology*; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D004224:Diterpenes; D004852:Epoxy Compounds; D010616:Phenanthrenes; D051844:alpha-Synuclein; C001899:triptolide
keywords: Autophagy; Neuron; Parkinson’s disease; Triptolide; α-Synuclein