Impairment of autophagy-lysosomal pathway in Parkinson's disease: Novel roles of HMGB1-TFEB interplay and therapeutic implication of Chinese medicine compounds

Project: Research project

Project Details


Parkinson’s disease (PD) is the most common neurodegenerative movement disorder afflicting 7-10 million people worldwide. Progressive loss of dopaminergic neurons and accumulation of abnormal protein aggregates including α-synuclein (SNCA) in the midbrain are the major pathological hallmarks of PD. Unfortunately, current drugs for PD only can replenish dopamine levels, without stopping the disease progression.

The autophagy–lysosomal pathway (ALP) is a cellular machinery responsible for degradation of protein aggregates and damaged organelles. Transcription factor EB (TFEB) and high-mobility group box 1 (HMGB1) are two positive regulators of ALP. Notably, reduced levels of TFEB and HMGB1 were observed in the nuclei of dopaminergic neurons from PD patients. We and other investigators have previously demonstrated how SNCA and PD-causing neurotoxins inhibit ALP via deregulating TFEB or HMGB1. Importantly, we have discovered some natural compounds or their derivatives from Chinese medicine which can target HMGB1 or TFEB to promote ALP, thus attenuating PD pathology in animal models. Then we raised a key question whether both HMGB1 and TFEB need to be activated for potential PD therapy. In our pilot study, we found that: 1) HMGB1 and TFEB physiologically interacts with each other in vitro and in vivo; 2) small-molecule TFEB activators promote the binding of TFEB to HMGB1 in the nuclei; 3) HMGB1 and TFEB interdependently regulate autophagy and lysosome biogenesis; 4) Wild-type (WT) and A53T-mutated SNCA bind to both HMGB1 and TFEB; and 5) Overexpressed SNCA inhibits HMGB1-TFEB interaction. Based on these new data, we hypothesize that defective HMGB1-TFEB interaction in the dopaminergic neurons leads to the ALP impairment and accumulation of toxic protein aggregates in PD, and a combination of Chinese medicine compounds targeting both HMGB1 and TFEB may hold better promise for PD therapy.

In this proposal, we will test this hypothesis through fulfilling three specific objectives: (1) To validate whether HMGB1 is a transcriptional co-activator of TFEB; (2) To dissect the roles of HMGB1-TFEB interaction in ALP impairment induced by overexpressed SNCA and the neurotoxin MPTP in vitro and in vivo; and 3) To evaluate the protective potential of combined Chinese medicine compounds targeting the HMGB1-TFEB complex in animal models of PD. The achievements of this study will advance our current understanding on the regulatory mechanisms of HMGB1-TFEB complex in ALP, reveal its key roles in the pathogenesis of PD, and more importantly, provide a rationale drug development strategy for PD treatment by targeting HMGB1-TFEB complex.
Effective start/end date1/01/2331/12/25

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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