Corynoxine B targets at HMGB1/2 to enhance autophagy for α-synuclein clearance in fly and rodent models of Parkinson's disease

Zhu，Qi1; Song，Juxian2,3; Chen，Jia Yue1; Yuan，Zhenwei3; Liu，Liangfeng3,4,5; Xie，Li Ming1; Liao，Qiwen6; Ye，Richard D.6; Chen，Xiu1; Yan，Yepiao1; Tan，Jieqiong7; Heng Tan，Chris Soon8; Li，Min3; Lu，Jia Hong1

2023

10.1016/j.apsb.2023.03.011

Acta Pharmaceutica Sinica B   Impact Factor & Quartile

2211-3835

2211-3843

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.

Autophagy Corynoxine B HMGB1 HMGB2 Neurodegenerative disease Parkinson's disease PI3KC3 α-Synuclein

English

Others

Science and Technology Development Fund[0128/2019/A3];Basic and Applied Basic Research Foundation of Guangdong Province[2022A1515012416];National Natural Science Foundation of China[82271455];Hong Kong Baptist University[HKBU/RC-IRCs/17-18/03];Hong Kong Baptist University[IRCMS/19-20/H02];Universidade de Macau[MYRG2022-00094-ICMS];Shenzhen Fundamental Research Program[SGDX20210823103804030];

2-s2.0-85151490494

Scopus

1.State Key Laboratory of Quality Research in Chinese Medicine,Institute of Chinese Medical Sciences,University of Macau,Macao,999078,China
2.Medical College of Acupuncture-Moxibustion and Rehabilitation,Guangzhou University of Chinese Medicine,Guangzhou,510006,China
3.Mr. and Mrs. Ko Chi Ming Centre for Parkinson's Disease Research,School of Chinese Medicine,Hong Kong Baptist University,HongKong,999077,China
4.Guangdong Corporate Key Laboratory of High-end Liquid Medicine R&D,Industrialization,Shaoguan,512028,China
5.Limin Pharmaceutical Factory,Livzon Pharmaceutical Group Inc.,Shaoguan,512028,China
6.Kobilka Institute of Innovative Drug Discovery,School of Medicine,The Chinese University of Hong Kong,Shenzhen,518172,China
7.Center for Medical Genetics,Life Science School,Central South University,Changsha,410031,China
8.Department of Chemistry,College of Science,Southern University of Science and Technology,Shenzhen,518055,China

Zhu，Qi,Song，Juxian,Chen，Jia Yue,et al. Corynoxine B targets at HMGB1/2 to enhance autophagy for α-synuclein clearance in fly and rodent models of Parkinson's disease[J]. Acta Pharmaceutica Sinica B,2023.

Zhu，Qi.,Song，Juxian.,Chen，Jia Yue.,Yuan，Zhenwei.,Liu，Liangfeng.,...&Lu，Jia Hong.(2023).Corynoxine B targets at HMGB1/2 to enhance autophagy for α-synuclein clearance in fly and rodent models of Parkinson's disease.Acta Pharmaceutica Sinica B.

Zhu，Qi,et al."Corynoxine B targets at HMGB1/2 to enhance autophagy for α-synuclein clearance in fly and rodent models of Parkinson's disease".Acta Pharmaceutica Sinica B (2023).