3-Anhydro-6-hydroxy-ophiobolin A, a fungal sesterterpene from Bipolaris oryzae induced autophagy and promoted the degradation of α-synuclein in PC12 cells.
Autophagy is defined as an evolutionarily conserved process responsible for degradation of the cytoplasmic components including protein aggregates via the lysosomal machinery. Increasing evidence has linked defective autophagic degradation of protein aggregates with the pathogenesis of neurodegenerative disorders, and it is suggested that promotion of autophagy is regarded as a potential therapeutic for these diseases including Parkinson's disease (PD). Here we identified, 3-anhydro-6-hydroxy-ophiobolin A (X15-2), an ophiobolin derivative from Bipolaris oryzae that can strongly induce autophagic degradation of α-synuclein, the major constituent of Lewy bodies. We showed that X15-2 induced autophagy is dependent on both Beclin1 and Beclin2. Knockout of ATG5 by CRISPER/Cas9 prevented X15-2 induced autophagy and degradation of α-synuclein. Mechanistically, we showed that X15-2 induces ROS and the activation of JNK signaling for the autophagic degradation of α-synuclein in PC12 cells.
State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100101, China.
Danfeng
D
Xue
State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
Quanxin
Q
Wang
State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100101, China.
Ziheng
Z
Chen
State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
Lei
L
Cai
State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
Li
L
Bao
State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
Qiuyue
Q
Qi
State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100101, China.
Lei
L
Liu
State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
Xiaohui
X
Wang
State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
Haijing
H
Jin
State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
Jun
J
Wang
State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100101, China. Electronic address: wuhao@ioz.ac.cn.
Hao
H
Wu
State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China. Electronic address: liuhw@im.ac.cn.
Hongwei
H
Liu
State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100101, China; Tianjin Key Laboratory of Protein Science, College of Life Sciences, Nankai University, Tianjin 300071, China. Electronic address: chenq@ioz.ac.cn.
Quan
Q
Chen
D000818:Animals; D001203:Ascomycota / Q000737:chemistry*; D001343:Autophagy / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006367:HeLa Cells; D006801:Humans; D008968:Molecular Conformation; D016716:PC12 Cells; D046188:Protein Modification, Translational / Q000187:drug effects*; D059748:Proteolysis / Q000187:drug effects*; D051381:Rats; D054830:Sesterterpenes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D051844:alpha-Synuclein / Q000378:metabolism*
C000603598:3-anhydro-6-hydroxyophiobolin A; D054830:Sesterterpenes; D051844:alpha-Synuclein
3-Anhydro-6-hydroxy-ophiobolin A; Autophagy; ROS; α-Synuclein