| Title | Discovery of a molecular glue that enhances UPR~(mt) to restore proteostasis via TRKA-GRB2-EVI1-CRLS1 axis |
| Authors | Li-Feng-Rong Qi Shuai Liu Qiuyuan Fang Cheng Qian Chao Peng Yuci Liu Peng Yang Ping Wu Ling Shan Qinghua Cui Liangyi Chen Wei Yang Ping Li Xiaojun Xu |
| Affiliation | State Key Laboratory of Natural Medicines, China Pharmaceutical University Department of Biophysics, and Department of Neurosurgery of the First Affiliated Hospital, Zhejiang University School of Medicine National Facility for Protein Science in Shanghai, Zhangjiang Lab, Shanghai Advanced Research Institute, Chinese Academy of Science Shanghai Science Research Center, Chinese Academy of Sciences Dept.Neuropsychiatric Disorders, Netherlands Institute for Neuroscience, An Institute of the Royal Netherlands Academy of Arts and Sciences 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 PKU-IDG/McGovern Institute for Brain Research |
| Keywords | Parkinson''s disease cardiolipin UPR~(mt) Ginsenoside Rg3 GRB2 TRKA EVI1 |
| Issue Date | 2-Dec-2022 |
| Publisher | 2022生物物理大会摘要集 |
| Abstract | Lowering proteotoxicity is a potentially powerful approach for the treatment of neurological disorders, such as Parkinson's disease. The unfolded protein response(UPR) is a major mechanism that preserves the network maintaining cellular proteostasis. In the present study, we developed the screening strategy to discover compounds that significantly enhanced the activation of mitochondrial UPR(UPRmt)through increasing cardiolipin content. We identified that ginsenoside Rg3(Rg3)increased cardiolipin depending on cardiolipin synthase 1(CRLS1) in both worms and in human neural cells. Using LiP-SMap(limited proteolysis-mass spectrometry)strategy, we identified GRB2(growth factor receptor bound protein 2) as a direct target of Rg3 in human neural cells. Rg3 enhances the binding between GRB2 and TRKA(tropomyosin-related kinase A), that transduces signals via phosphrorylation of ERK(extracellular signal-regulated kinase). We provided bioinformatic and experimental evidences showing that EVI1(ecotropic virus integration site-1), the critical oncogenic transcriptional regulator in leukemia, binds to CRLS1 promoter region and stimulated CRLS1 expression and subsequently increased cardiolipin content in the presence of Rg3. Rg3 stimulates alpha-synuclein clearance by promoting mitochondrial peripheral fission and mitophagy. In two Parkinson's disease mouse models, Rg3 restores motor function by protecting nigral dopaminergic neurons dependent on GRB2. Consistently, Rg3 protected iPSC-derived dopaminergic neurons by restoring ERK/CRLS1 signaling and mitochondrial function. Our data recapitulate the TRKA-GRB2-EVI1-CRLS1 axis in maintaining proteostasis in Parkinson's disease via restoring mitochondrial homeostasis. |
| URI | http://hdl.handle.net/20.500.11897/672276 |
| Appears in Collections: | 医学部待认领 |
