研究成果 |
一、基本情况 聚焦神经退行性疾病致病蛋白（如α-syn、TDP-43等）的相变聚集研究，围绕其化学基础、动态调控机制及小分子抑制剂与示踪剂的开发，取得了一系列具有国际影响力的原创成果。揭示了帕金森病潜在的多个新靶点，靶向α-syn病理聚集体成功开发致病蛋白聚集体小分子PET示踪剂，已完成100余例IIT临床试验并进入一期临床研究，展现出良好的临床转化前景。 近年来，以通讯作者身份在 Cell、Science、Nat Chem Biol、Nat Struct & Mol Biol、PNAS、Cell Research、Angew Chem Int Edit等高水平期刊发表论文80余篇。此外，受邀为Cell、Nat Rev Neurosci、Nat Chem Biol、Trends系列、Mol Cell、Chemical Reviews、Chemical Society Reviews等撰写蛋白聚集结构多态性在神经退行性疾病中作用的综述与评论性论文。主持和参与多个国家级与省部级重大科研项目，包括国家自然科学基金委基础科学中心项目、国家杰出青年科学基金、科技部重点研发计划及蛋白质重大专项、科技部青年863计划、上海科委重大专项等。 二、代表性论文 1. Zeng S, Zhang S, Zhang S, Fan Y, Xia W, Chen F, Huang C, Lv S, Lu J, Sun Y, Liu K, Li Y, Zhang Y, Wang J*, Liu C*, Li D*. TPPP/p25 amyloid seeding activity as a specific biomarker for multiple system atrophy. Cell. (2026) 189(15): 4724-4736. 2. Neuronal FAM171A2 mediates α-synuclein fibril uptake and drives Parkinson's disease. Wu KM, Xu QH, Liu YQ, Feng YW, Han SD, Zhang YR, Chen SD, Guo Y, Wu BS, Ma LZ, Zhang Y, Chen YL, Yang L, Yang ZF, Xiao YJ, Wang TT, Zhao J, Chen SF, Cui M, Lu BX, Le WD, Shu YS, Ye K, Li JY, Li WS, Wang J, Liu C*，Yuan P*, Yu JT*. Science.（2025）387(6736):892-900. 3. Quantitative chemoproteomics reveals dopamine's protective modification of Tau. Wang Q, Liu Z, Wang Y, Liu Y, Chen Y, Zhang S, Zeng W, Li D, Yang F, He Z, Xiao W*, Liu C*，Wang C*. Nat Chem Biol.（2025）doi: 10.1038/s41589-025-01849-9 4. MEK1/2 inhibitors suppress pathological α-synuclein and neurotoxicity in cell models and a humanized mouse model of Parkinson's disease. Wang H, Wang Q, Xu H, Wu Y, Cheung S, Xu Q, Pan C, Cao J, Cao Z, Yang R, Ding Y, Fei Y, Chen Y, Wang J*, Liu C*，Lu B*. Sci Transl Med. (2025）17(798):eadp4625. 5. Time-course remodeling and pathology intervention of α-synuclein amyloid fibril by heparin and heparin-like oligosaccharides. Tao Y, Xu P, Zhang S, Shangguan W, Yang G, Liu K, Li X, Sun Y, Zhao Q, Li D, Yu B*, Liu C*. Nat Struct Mol Biol. (2025) 32(2):369-380. doi: 10.1038/s41594-024-01407-2 6. Design and Structural Elucidation of Glycopeptide Fibrils: Emulating Glycosaminoglycan Functions for Biomedical Applications. Xia W, Xu Z, Dong H, Zhang S, He C, Li D, Sun B, Dai B, Dong S*, Liu C*. J Am Chem Soc. (2025). doi: 10.1021/jacs.5c07039 7. α-Synuclein amyloid fibril directly binds to LC3B and suppresses SQSTM1/p62-mediated selective autophagy. Xu Q, Wang H, Yang R, Tao Y, Wang Z, Zhang S, Sun B, Li D, Lu B*, Liu C*. Cell Research. (2024) doi: 10.1038/s41422-024-01022-2 8. Inhibitor Development for α-Synuclein Fibril's Disordered Region to Alleviate Parkinson's Disease Pathology. Zhang S, Xiang H, Tao Y, Li J, Zeng S, Xu Q, Xiao H, Lv S, Song C, Cheng Y, Li M, Zhu Z, Zhang S, Sun B, Li D, Xiang S*, Tan L*, Liu C*. J Am Chem Soc. (2024). doi: 10.1021/jacs.4c08869. 9. Binding adaptability of chemical ligands to polymorphic α-synuclein amyloid fibrils. Liu K, Tao Y, Zhao Q, Xia W, Li X, Zhang S, Yao Y, Xiang H, Han C, Tan L, Sun B, Li D, Li A, Liu C*. Proc Natl Acad Sci U S A. (2024) 121(35):e2321633121. 10. Lysophosphatidylcholine binds α-synuclein and prevents its pathological aggregation. Zhao C, Tu J, Wang C, Liu W, Gu J, Yin Y, Zhang S, Li D, Diao J*, Zhu ZJ*, Liu C*. National Science Review. (2024). 11(6):nwae182 11. Phosphorylation-Regulated Dynamic Phase Separation of HIP-55 Protects Against Heart Failure. 🗍Jiang Y, Gu J, Niu X, Hu J, Zhang Y, Li D, Tang Y, Liu C*, Li Z*. Circulation. (2024) , 150(12):938-951 12. Structural mechanism for specific binding of chemical compounds to protein amyloid fibril. Tao Y, Xia W, Zhao X, Tang W, Li Y, Tan L, Li D*, Liu C*. Nature Chemical Biology. (2023) doi.10.1038/s41589-023-01370-x 13. Rational design of functional amyloid fibrillar assemblies. Wang X, Zhang S, Zhang J, Wang Y, Jiang X, Tao Y, Li D, Zhong C*, Liu C*. Chem Soc Rev. (2023) Jun 21. doi: 10.1039/d2cs00756h. (Invited review） 14. Conformational Dynamics of an α-Synuclein Fibril upon Receptor Binding Revealed by Insensitive Nuclei Enhanced by Polarization Transfer-Based Solid-State Nuclear Magnetic Resonance and Cryo-Electron Microscopy. Zhang S, Li J, Xu Q, Xia W, Tao Y, Shi C, Li D, Xiang S*, Liu C*. J Am Chem Soc. (2023) Mar 1;145(8):4473-4484. 15. Advanced Techniques for Detecting Protein Misfolding and Aggregation in Cellular Environments. Bai Y, Zhang S, Dong H, Liu Y, Liu C*, Zhang X*. Chem Rev. (2023) Nov 8;123(21):12254-12311. (Invited review） 16. Emerging roles of O-glycosylation in regulating protein aggregation, phase separation, and functions. Li X, Pinou Lv, Du Y, Chen X*, Liu C*, Curr Opin Chem Biol. (2023) Aug;75:102314. (Invited review） 17. Creating an Amyloid 'Kaleidoscope' Using Short Iodinated Peptides. Li D, Ma Y, Xia W, Tao Y, Zhang Y, Zhang H, Li D, Dai B*, Liu C*, Angew Chem Int Ed Engl. (2023) Oct 16;62(42): 18. Global profiling of arginine dimethylation in regulating protein phase separation by a steric effect-based chemical-enrichment method. Wang Q, Li Z, Zhang S, Li Y, Wang Y, Fang Z, Ma Y, Liu Z, Zhang W, Li D, Liu C*, Ye M*. Proc Natl Acad Sci U S A. (2022) Oct 25;119(43) 19. Bloom Syndrome Helicase Compresses Single-Stranded DNA into Phase-Separated Condensates. Wang T, Hu J, Li Y, Bi L, Guo L, Jia X, Zhang X, Li D, Hou XM, Modesti M, Xi XG, Liu C*, Sun B*. Angew Chem Int Ed Engl. (2022) Sep 26;61(39) 20. Conformational strains of pathogenic amyloid proteins in neurodegenerative diseases. Li D, Liu C*. Nature Reviewers Neuroscience. (2022) May 30. (Invited review） 21. Heparin induces α-synuclein to form new fibril polymorphs with attenuated neuropathology. Tao Y, Sun Y, Lv S, Xia W, Zhao K, Xu Q, Zhao Q, He L, Le W, Wang Y, Liu C*, Li D*. Nature Communications. (2022) Jul 22;13(1):4226. 22. Cryo-EM structure of an amyloid fibril formed by full-length human SOD1 reveals its conformational conversion. Wang LQ, Ma Y, Yuan HY, Zhao K, Zhang MY, Wang Q, Huang X, Xu WC, Dai B, Chen J, Li D, Zhang D, Wang Z, Zou L, Yin P, Liu C*, Liang Y*. Nature Communications. (2022). Jun 17;13(1):3491. 23. Liquid-liquid phase separation of RBGD2/4 is required for heat stress resistance in Arabidopsis. Zhu S, Gu J, Yao J, Li Y, Zhang Z, Xia W, Wang Z, Gui X, Li L, Li D, Zhang H*, Liu C*. Developmental Cell. (2022) Mar 14;57(5):583-597. 24. Generic amyloid fibrillation of TMEM106B in patient with Parkinson's disease dementia and normal elders. Fan Y, Zhao Q, Xia W, Tao Y, Yu W, Chen M, Liu Y, Zhao J, Shen Y, Sun Y, Si C, Zhang S, Zhang Y, Li W, Liu C*, Wang J*, Li D*. Cell Research. (2022) Jun;32(6):585-588. 25. O-Glycosylation Induces Amyloid-β To Form New Fibril Polymorphs Vulnerable for Degradation. Liu D, Wei Q, Xia W, He C, Zhang Q, Huang L, Wang X, Sun Y, Ma Y, Zhang X, Wang Y, Shi X, Liu C*, Dong S*. J Am Chem Soc. (2021) Dec 8;143(48):20216-20223. 26. The hereditary mutation G51D unlocks a distinct fibril strain transmissible to wild-type α-synuclein. Sun Y, Long H, Xia W, Wang K, Zhang X, Sun B, Cao Q, Zhang Y, Dai B, Li D, Liu C*. Nature Communications. (2021).12(1):6252. 27. Spatiotemporal dynamic regulation of membraneless organelles by chaperone networks. Li D*, Liu C*. Trends Cell Biol. (2021). S0962-8924(21)00165-3.(Invited forum). 28. Genetic prion disease-related mutation E196K displays a novel amyloid fibril structure revealed by cryo-EM. Wang LQ, Zhao K, Yuan HY, Li XN, Dang HB, Ma Y, Wang Q, Wang C, Sun Y, Chen J, Li D, Zhang D, Yin P, Liu C*, Liang Y*. Science Advances. (2021). 7(37): eabg9676. 29. Hsp70 chaperones TDP-43 in dynamic, liquid-like phase and prevents it from amyloid aggregation Gu J.G., Wang C., Hu R.F., Li Y.C., Zhang S.N., Sun Y.P., Wang Q.Q., Li D., Fang Y.S.*, Liu C.*. Cell Research. (2021). 1024-1027. 30. Mechanistic basis for receptor-mediated pathological α-synuclein fibril cell-to-cell transmission in Parkinson's disease. Zhang S.N, Liu Y.Q, Jia C.Y, Lim Y.J, Feng G.Q, Xu E.Q., Long H.F., Yasuyoshi Kimura, Tao Y.Q., Zhao C.Y., Wang C.C., Liu Z.Y., Hu J.J., Ma M.R., Liu Z.J., Lin J., Li D., Wang R.X., Valina L Dawson, Ted M Dawson*, Li Y.M.*, Mao X.B.*, Liu C.*. Proc. Natl. Acad. Sci. U S A., (2021). 118(26): e2011196118. 31. Wild-type α-synuclein inherits the structure and exacerbated neuropathology of E46K mutant fibril strain by cross-seeding. Long H.F., Zheng W.T., Liu Y., Sun Y.P., Zhao K., Liu Z.Y., Xia W.C., Lv S.R., Liu Z.T., Li D., He K.W.*, Liu C.*. Proc. Natl. Acad. Sci. U S A., (2021). 118(20): e2012435118. 32. The structure of a minimum amyloid fibril core formed by necroptosis-mediating RHIM of human RIPK3. Wu X.L, Ma Y.Y., Zhao K., Zhang J., Sun Y.P., Li Y.C., Dong X.Q., Hu H., Liu J., Wang J., Zhang X., Li B., Wang H.Y., Li D., Sun B., Lu J.X.*, Liu C.*. Proc. Natl. Acad. Sci. U S A., (2021). 118(14): e2022933118. 33. Hierarchical chemical determination of amyloid polymorphs in neurodegenerative disease. Li D*, Liu C*. Nature Chemical Biology. (2021). 17(3):237-245. (Invited review). 34. The nuclear localization sequence mediates hnRNPA1 amyloid fibril formation revealed by cryoEM structure. Sun Y, Zhao K, Xia W, Feng G, Gu J, Ma Y, Gui X, Zhang X, Fang Y, Sun B, Wang R, Liu C*, Li D*. Nature Communications, (2020). 11(1):6349. 35. Hsp40 proteins phase separate to chaperone the assembly and maintenance of membraneless organelles. Gu J, Liu Z, Zhang S, Li Y, Xia W, Wang C, Xiang H, Liu Z, Tan L, Fang Y, Liu C*, Li D*. Proc Natl Acad Sci U S A. (2020). 117(49):31123-31133. 36. Phase separation of protein tyrosine phosphatase underlies MAPK hyperactivation by disease-associated SHP2 mutants. Zhu G, Xie J, Kong W, Xie J, Li Y, Du L, Zheng Q, Sun L, Guan M, Li H, Zhu T, He H, Liu Z, Xia X, Kan C, Tao Y, Shen H, Li D, Wang S, Yu Y, Yu Z, Zhang Z, Liu C*, Zhu J*. Cell. (2020). 183(2):490-502.e18. 37. Stress Induces Dynamic, Cytotoxicity-Antagonizing TDP-43 Nuclear Bodies via Paraspeckle LncRNA NEAT1-Mediated Liquid-Liquid Phase Separation. Wang C, Duan Y, Duan G, Wang Q, Zhang K, Deng X, Qian B, Gu J, Ma Z, Zhang S, Guo L, Liu C*, Fang Y*. Molecular Cell. (2020). 79(3):443-458.e7 38. Parkinson's disease-related phosphorylation at Tyr39 rearranges α-synuclein amyloid fibril structure revealed by cryo-EM. Zhao K, Lim YJ, Liu Z, Long H, Sun Y, Hu JJ, Zhao C, Tao Y, Zhang X, Li D, Li YM*, Liu C*. Proc Natl Acad Sci U S A. (2020). 117(33): 20305-20315. 39. Hsp27 chaperones FUS phase separation under the modulation of stress-induced phosphorylation. Liu Z.Y., Zhang S.N., Gu J.G., Tong Y.L., Li Y.C., Gui X.R., Long H.F., Wang C.C., Zhao C.Y., Lu J.X., He L., Li Y., Liu Z.J., Li D*., Liu C*. Nature Structural & Molecular Biology, (2020). 27(4):363-372. 40. Cryo-EM structure of an amyloid fibril formed by full-length human prion protein. Wang L.Q., Zhao K., Yuan H., Wang Q., Guan Z., Tao J., Li L., Sun Y.P., Yi C.W., Chen J., Li D., Zhang D., Yin P., Liu C*., Liang Y*. Nature Structural & Molecular Biology, (2020). 27(6):598-602. 41. Different regions of synaptic vesicle membrane regulate VAMP2 conformation for the SNARE assembly. Wang C.C., Tu J., Zhang S.N., Cai B., Liu Z.Y., Hou S.Q., Zhong Q.L., Hu X., Liu W.B., Li G.H., Liu Z.J., He L., Diao J.J., Zhu Z.J., Li D.*, Liu C.*. Nature Communications, (2020), 11(1):1531. 42. Parkinson’s disease associated mutation E46K of α-synuclein triggers the formation of a novel fibril structure. Zhao K., Li Y.W., Liu Z.Y., Long H., Zhao C.Y., Luo F., Sun Y.P., Tao Y.Q., Su X.D., Li D*., Li X.M.*, Liu C*. Nature Communications, (2020). 11(1):2643. 43. Cryo-EM structure of full-length α-synuclein amyloid fibril with Parkinson's disease familial A53T mutation. Sun Y.P., Hou S.Q., Zhao K., Long H.F., Liu Z.Y., Gao J., Zhang Y.Y., Su X.D., Li D.*, Liu C.*, Cell Research, 2020, 0, 1-3. 二、主持的国家及省部级科研项目 1. 国家杰出青年科学基金项目，蛋白质相分离与相变的化学调控 2. 尚思系列学者科研资助经费，尚思探索学者 3. 上海市科学技术委员会，2022年东方英才计划领军项目 |
