TY - JOUR
T1 - Corynoxine B targets at HMGB1/2 to enhance autophagy for α-synuclein clearance in fly and rodent models of Parkinson's disease
AU - Zhu, Qi
AU - Song, Juxian
AU - Chen, Jia Yue
AU - Yuan, Zhenwei
AU - Liu, Liangfeng
AU - Xie, Li Ming
AU - Liao, Qiwen
AU - Ye, Richard D.
AU - Chen, Xiu
AU - Yan, Yepiao
AU - Tan, Jieqiong
AU - Heng Tan, Chris Soon
AU - Li, Min
AU - Lu, Jia Hong
N1 - This study was supported by the National Natural Science Foundation of China (No. 82271455), the Guangdong Basic and Applied Basic Research Foundation (No. 2022A1515012416, China), the Science and Technology Development Fund, Macau SAR (No. 0128/2019/A3, China), the Shenzhen Fundamental Research Program (No. SGDX20210823103804030, China) and the University of Macau grants (No. MYRG2022-00094-ICMS, China) awarded to Jia-hong Lu. The study also partly supported by Hong Kong Health and Medical Research Fund (HMRF/17182551, HMRF/09203776, China) and the Hong Kong General Research Fund (HKBU 12100618, HKBU 12101022, China) from Hong Kong Government and the Research Fund from Hong Kong Baptist University (HKBU/RC-IRCs/17-18/03, IRCMS/19-20/H02, China) awarded to Min Li.
Publisher Copyright:
© 2023 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.
PY - 2023/6
Y1 - 2023/6
N2 - Parkinson's disease (PD) is the most common neurodegenerative movement disease. It is featured by abnormal alpha-synuclein (α-syn) aggregation in dopaminergic neurons in the substantia nigra. Macroautophagy (autophagy) is an evolutionarily conserved cellular process for degradation of cellular contents, including protein aggregates, to maintain cellular homeostasis. Corynoxine B (Cory B), a natural alkaloid isolated from Uncaria rhynchophylla (Miq.) Jacks., has been reported to promote the clearance of α-syn in cell models by inducing autophagy. However, the molecular mechanism by which Cory B induces autophagy is not known, and the α-syn-lowering activity of Cory B has not been verified in animal models. Here, we report that Cory B enhanced the activity of Beclin 1/VPS34 complex and increased autophagy by promoting the interaction between Beclin 1 and HMGB1/2. Depletion of HMGB1/2 impaired Cory B-induced autophagy. We showed for the first time that, similar to HMGB1, HMGB2 is also required for autophagy and depletion of HMGB2 decreased autophagy levels and phosphatidylinositol 3-kinase III activity both under basal and stimulated conditions. By applying cellular thermal shift assay, surface plasmon resonance, and molecular docking, we confirmed that Cory B directly binds to HMGB1/2 near the C106 site. Furthermore, in vivo studies with a wild-type α-syn transgenic drosophila model of PD and an A53T α-syn transgenic mouse model of PD, Cory B enhanced autophagy, promoted α-syn clearance and improved behavioral abnormalities. Taken together, the results of this study reveal that Cory B enhances phosphatidylinositol 3-kinase III activity/autophagy by binding to HMGB1/2 and that this enhancement is neuroprotective against PD.
AB - Parkinson's disease (PD) is the most common neurodegenerative movement disease. It is featured by abnormal alpha-synuclein (α-syn) aggregation in dopaminergic neurons in the substantia nigra. Macroautophagy (autophagy) is an evolutionarily conserved cellular process for degradation of cellular contents, including protein aggregates, to maintain cellular homeostasis. Corynoxine B (Cory B), a natural alkaloid isolated from Uncaria rhynchophylla (Miq.) Jacks., has been reported to promote the clearance of α-syn in cell models by inducing autophagy. However, the molecular mechanism by which Cory B induces autophagy is not known, and the α-syn-lowering activity of Cory B has not been verified in animal models. Here, we report that Cory B enhanced the activity of Beclin 1/VPS34 complex and increased autophagy by promoting the interaction between Beclin 1 and HMGB1/2. Depletion of HMGB1/2 impaired Cory B-induced autophagy. We showed for the first time that, similar to HMGB1, HMGB2 is also required for autophagy and depletion of HMGB2 decreased autophagy levels and phosphatidylinositol 3-kinase III activity both under basal and stimulated conditions. By applying cellular thermal shift assay, surface plasmon resonance, and molecular docking, we confirmed that Cory B directly binds to HMGB1/2 near the C106 site. Furthermore, in vivo studies with a wild-type α-syn transgenic drosophila model of PD and an A53T α-syn transgenic mouse model of PD, Cory B enhanced autophagy, promoted α-syn clearance and improved behavioral abnormalities. Taken together, the results of this study reveal that Cory B enhances phosphatidylinositol 3-kinase III activity/autophagy by binding to HMGB1/2 and that this enhancement is neuroprotective against PD.
KW - Autophagy
KW - Corynoxine B
KW - HMGB1
KW - HMGB2
KW - Neurodegenerative disease
KW - Parkinson's disease
KW - PI3KC3
KW - α-Synuclein
UR - https://www.scopus.com/pages/publications/85151490494
U2 - 10.1016/j.apsb.2023.03.011
DO - 10.1016/j.apsb.2023.03.011
M3 - Journal article
AN - SCOPUS:85151490494
SN - 2211-3835
VL - 13
SP - 2701
EP - 2714
JO - Acta Pharmaceutica Sinica B
JF - Acta Pharmaceutica Sinica B
IS - 6
ER -
