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

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

  • Acta Pharm Sin B. 2023 Jun;13(6):2701-2714. doi: 10.1016/j.apsb.2023.03.011.
Qi Zhu 1,  Juxian Song 2 3,  Jia-Yue Chen 1,  Zhenwei Yuan 3,  Liangfeng Liu 3 4 5,  Li-Ming Xie 1,  Qiwen Liao 6,  Richard D Ye 6,  Xiu Chen 1,  Yepiao Yan 1,  Jieqiong Tan 7,  Chris Soon Heng Tan 8,  Min Li 3,  Jia-Hong Lu 1
Affiliations

Affiliations

  • 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.
PMID: 37425041 DOI: 10.1016/j.apsb.2023.03.011
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.

Keywords

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

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