The research of Liu laboratory focuses on the mechanisms of protein phase separation and pathological protein aggregation in neurodegenerative diseases (NDs). The key pathological hallmarks of neurodegenerative diseases are the formation and accumulation of misfolded proteins, that were previously only known to be consisted of β-sheet rich forms of proteins with self-assembly and self-propagation properties similar to that of prions. Using exciting new technologies that were developed in his lab, Dr. Liu made a series of interesting and surprisingly systematic discoveries on the mechanisms of amyloid protein structure, formation, propagation and neurodegeneration. Studying amyloid structures are highly challenging and require special expertise: currently there are only a handful labs around the world that can do this. To overcome the existing technological limitations for studying the structures of amyloid fibers, Dr. Liu developed cryo-EM based helical 3D reconstruction method and electron diffraction method for nano-sized 3D crystals (micro-ED) which can overcome the technical challenges due to the tiny sizes of amyloid crystals and insoluble nature of amyloid fibrils. These new technologies advanced our ability to decipher the structures of pathological proteins in the misfolded amyloid fibrillar state which is not accessible by traditional structural biology tools. Using these technologies, Dr. Liu discovered that the atomic structures of protein amyloids are much more complex and dynamic than previously appreciated. He revealed the surprising dynamic structural polymorphs of pathological amyloid fibrils (e.g. α-synuclein and FUS), and uncovered the fundamental principles of protein folding in pathological fibrillar state which is distinct from the proteins in native state.  He discovered that different polymorphic fibrils exhibit distinct pathological properties, which provides a framework for us to further explore the mechanisms of the clinicopathological heterogeneity of PD and other neurodegenerative disorders and has important implications for developing therapeutic strategies. Furthermore, he discovered that the dynamic structural polymorphs of pathological amyloid fibril are subject to posttranslational modifications including phosphorylation, PARylation, and molecular chaperones (Hsp27, Hsp40) which have important impact on the stability and pathological properties of amyloids. Taken together, by combining interdisciplinary chemical and biological approaches, Dr. Liu revealed the structural basis of protein pathological aggregation in NDs, demonstrated the regulatory mechanisms of protein aggregation by disease-related post-translational modification, developed new strategies of designing small molecules to modulate protein phase separation for therapeutic application. 

In the past 5 years, as the corresponding or co-corresponding author, Dr. Liu published over 40 SCI papers, including Cell, PNAS (6), Nat Struct & Mol Biol (3), JACS, Cell Research (5), Nat Commun (7), Angew, Mol Cell, Dev Cell, and Sci Adv. His systematical findings on protein phase separation and aggregation in NDs have been well recognized internationally in the field, and he has been invited by Nat Chem Biol and Nat Rev Neurosci to write reviewing articles for introducing the structural polymorphism of amyloid aggregation and its hierarchical chemical determination in NDs. Dr. Liu’s work is supported by several highly competitive grants including the Key project of the Natural Science Foundation of China, the Major State Basic Research Development Program, the National 863 Major Scientific Project, overseas high-level talents, Shanghai outstanding academic leaders. Dr. Liu has also been invited to give presentations in EMBL/EMBO meetings, Gordon conference, and has been served as an international reviewer for foundations of Medical Research Council (MRC, UK), European Research Council (ERC) and others.