Understanding the molecular mechanisms of Corynoxine B in promoting autophagy and neuroprotection: Targeting HMGB1-Beclin 1 interaction

Project: Research project

Project Details


Parkinson’s disease (PD) is the second most common neurodegenerative disorder, affecting nearly 2 million people in mainland China and about 0.5% of the population aged over 55 in Hong Kong. The prevalence of PD in China is predicted to increase to 4.94% by 2030. PD represents an increasingly serious threat to quality of life, and an increasingly heavy burden on the health care system. Finding an effective therapy would help millions. Accumulation of alpha-synuclein (α-syn) protein in Lewy bodies (LB) in dopaminergic neurons is a hallmark of PD and thus increased α-syn level is pathogenic. Macroautophagy (autophagy) is an evolutionarily conserved cellular process for degradation of cellular contents, including protein aggregates and damaged cellular organelles to maintain cellular homeostasis. Increasing evidence suggests that autophagy plays a role in the clearance of disease-associated proteins (including mutant α-syn) and the deregulation of the autophagy pathway may promote PD-related pathologies in the brains of PD patients and in animal models of PD. Promoting autophagy to remove the toxic protein aggregates may provide disease-modifying therapies for PD.

Beclin 1 has a central role in autophagy regulation. It interacts with multiple proteins in PI3K III complex to control autophagic activity. High mobility group box 1 (HMGB1) is a nuclear protein that transports to cytoplasm and interacts with Beclin 1 to positively regulate autophagy. The applicants have identified new components in the Beclin 1-Vps34 protein complexes, revealed their distinct roles in autophagy regulation and resolved the structural basis for Beclin 1 and its binding partners (Zhong Y, et al., Nature Cell Biology 2009; Li X, et al., Nature Communications 2012).

Recently, we identified a Beclin 1-dependent autophagy inducer namely Corynoxine B (Cory B) from the neurotrophic Chinese herb Gouteng (鉤藤) which efficiently promotes the clearance of α-syn in multiple cellular models of PD (Lu JH, et al. Autophagy 2012; Patent No.: US 13/420,628) (funded by RGC-NSFC/11-12). Moreover, we have demonstrated that α-syn overexpression impairs HMGB1/Beclin 1-mediated autophagy in cell models of PD, and Cory B rescues autophagy possibly through modulating HMGB1-Beclin 1 pathway (Song JX, et al., Autophagy 2013). Furthermore, we have obtained a series of preliminary data showing that: (1) Cory B directly binds to HMGB1; (2) Cory B promotes HMGB1-Beclin 1 interaction and (3) Cory B induces autophagy and prevents neurodegeneration in Drosophila and mice. With these encouraging results, we hypothesize that Cory B enhances the interaction between HMGB1 and Beclin 1 to promote autophagy and exert neuroprotection. To test the hypothesis, we propose: (1) to validate and dissect HMGB1-Beclin 1 interaction as the primary target of Cory B to induce autophagy; (2) to conduct structural characterization of the Cory B-HMGB1/Beclin 1 complex and (3) to evaluate HMGB1-Beclin 1 interaction in autophagy regulation and test the neuroprotective effect of Cory B in adeno-associated viral (AAV)-α-syn rat models.

The current proposal will validate the direct target of the pro-autophagy compound Cory B and lead to further drug development for the prevention and /or treatment of PD.
Effective start/end date1/01/1531/12/17

UN Sustainable Development Goals

In 2015, UN member states agreed to 17 global Sustainable Development Goals (SDGs) to end poverty, protect the planet and ensure prosperity for all. This project contributes towards the following SDG(s):

  • SDG 3 - Good Health and Well-being


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