2. Academic Validation
  3. Ginsenoside Rg3 Restores Mitochondrial Cardiolipin Homeostasis via GRB2 to Prevent Parkinson's Disease

Ginsenoside Rg3 Restores Mitochondrial Cardiolipin Homeostasis via GRB2 to Prevent Parkinson's Disease

  • Adv Sci (Weinh). 2024 Aug 19:e2403058. doi: 10.1002/advs.202403058.
Li-Feng-Rong Qi 1,  Shuai Liu 1 2,  Qiuyuan Fang 3,  Cheng Qian 1,  Chao Peng 4 5,  Yuci Liu 1,  Peng Yang 1,  Ping Wu 4 5,  Ling Shan 6,  Qinghua Cui 7,  Qian Hua 8,  Sen Yang 9,  Cunqi Ye 9,  Wei Yang 2,  Ping Li 1,  Xiaojun Xu 1 2
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, 210009, China.
  • 2 Department of Pharmacy, The Fourth Affiliated Hospital, Center for Innovative Traditional Chinese Medicine Target and New Drug Research, International Institutes of Medicine, Zhejiang University School of Medicine, Yiwu, Zhejiang, 322000, China.
  • 3 Department of Biophysics and Department of Neurosurgery of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China.
  • 4 National Facility for Protein Science in Shanghai, Zhangjiang Lab, Shanghai Advanced Research Institute, Chinese Academy of Science, Shanghai, 201210, China.
  • 5 Shanghai Science Research Center, Chinese Academy of Sciences, Shanghai, 201204, China.
  • 6 Dept. Neuropsychiatric Disorders, Netherlands Institute for Neuroscience, An Institute of the Royal Netherlands Academy of Arts and Sciences, Meibergdreef 47, Amsterdam, 1105BA, the Netherlands.
  • 7 Department of Biomedical Informatics, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Sciences of the Ministry of Education, Center for Non-Coding RNA Medicine, Peking University Health Science Center Beijing, Beijing, 100191, China.
  • 8 School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 100029, China.
  • 9 Life Sciences Institute, Zhejiang University, Hangzhou, 310058, China.
PMID: 39159293 DOI: 10.1002/advs.202403058
Abstract

Regulating cardiolipin to maintain mitochondrial homeostasis is a promising strategy for addressing Parkinson's disease (PD). Through a comprehensive screening and validation process involving multiple models, ginsenoside Rg3 (Rg3) as a compound capable of enhancing cardiolipin levels is identified. This augmentation in cardiolipin levels fosters mitochondrial homeostasis by bolstering mitochondrial unfolded protein response, promoting Mitophagy, and enhancing mitochondrial Oxidative Phosphorylation. Consequently, this cascade enhances the survival of tyrosine hydroxylase positive (TH+) dopaminergic neurons, leading to an amelioration in motor performance within PD mouse models. Using limited proteolysis-small-molecule mapping combined with molecular docking analysis, it has confirmed Growth Factor Receptor-Bound Protein 2 (GRB2) as a molecular target for Rg3. Furthermore, these investigations reveal that Rg3 facilitates the interaction between GRB2 and TrkA (Neurotrophic Tyrosine Kinase, Receptor, Type 1), thus promotes EVI1 (Ecotropic Virus Integration Site 1 Protein Homolog) phosphorylation by ERK, subsequently increases CRLS1 (Cardiolipin Synthase 1) gene expression and boosts cardiolipin synthesis. The absence of GRB2 or CRLS1 significantly attenuates the beneficial effects of Rg3 on PD symptoms. Finally, Tenofovir Disoproxil Fumarate (TDF) that also promotes the binding between GRB2 and TrkA is further identified. The identified compounds, Rg3 and TDF, exhibit promising potential for the prevention of PD by bolstering cardiolipin expression and reinstating mitochondrial homeostasis.

Keywords

CRLS1; EVI1; GRB2; TRKA; cardiolipin.

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