Corynoxine B targets at HMGB1/2 to enhance autophagy for α-synuclein clearance in fly and rodent models of Parkinson's disease.
10.1016/j.apsb.2023.03.011
- Author:
Qi ZHU
1
;
Juxian SONG
2
;
Jia-Yue CHEN
1
;
Zhenwei YUAN
3
;
Liangfeng LIU
3
;
Li-Ming XIE
1
;
Qiwen LIAO
4
;
Richard D YE
4
;
Xiu CHEN
1
;
Yepiao YAN
1
;
Jieqiong TAN
5
;
Chris Soon HENG TAN
6
;
Min LI
3
;
Jia-Hong LU
1
Author Information
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. Kobilka Institute of Innovative Drug Discovery, School of Medicine, the Chinese University of Hong Kong, Shenzhen 518172, China.
5. Center for Medical Genetics, Life Science School, Central South University, Changsha 410031, China.
6. Department of Chemistry, College of Science, Southern University of Science and Technology, Shenzhen 518055, China.
- Publication Type:Journal Article
- Keywords:
Autophagy;
Corynoxine B;
HMGB1;
HMGB2;
Neurodegenerative disease;
PI3KC3;
Parkinson's disease;
α-Synuclein
- From:
Acta Pharmaceutica Sinica B
2023;13(6):2701-2714
- CountryChina
- Language:English
-
Abstract:
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.
