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Hierarchical chemical determination of amyloid polymorphs in neurodegenerative disease


Amyloid aggregation, which disrupts protein homeostasis, is a common pathological event occurring in human neurodegenerative diseases (NDs). Numerous evidences have shown that the structural diversity, so-called polymorphism, is decisive to the amyloid pathology and is closely associated with the onset, progression, and phenotype of ND. But how could one protein form so many stable structures? Recently, atomic structural evidence has been rapidly mounting to depict the involvement of chemical modifications in the amyloid fibril formation. In this Perspective, we aim to present a hierarchical regulation of chemical modifications including covalent post-translational modifications (PTMs) and noncovalent cofactor binding in governing the polymorphic amyloid formation, based mainly on the latest α-synuclein and Tau fibril structures. We hope to emphasize the determinant role of chemical modifications in amyloid assembly and pathology and to evoke chemical biological approaches to lead the fundamental and therapeutic research on protein amyloid state and the associated NDs.

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Fig. 1: Environment-sensitive amyloid fibril formation of Tau and α-syn proteins.
Fig. 2: Schematic of the hierarchical regulation of chemical modifications to amyloid fibril assembly.
Fig. 3: Chemical modifications in the regulation of α-syn fibril conformations.
Fig. 4: Chemical modifications in regulation of brain-extracted Tau fibril conformations.


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This work was supported by the Major State Basic Research Development Program (2016YFA0501902 to C.L.), the National Natural Science Foundation (NSF) of China (91853113 and 31872716 to C.L. and D.L.), the Science and Technology Commission of Shanghai Municipality (18JC1420500 to C.L.), “Eastern Scholar” project supported by Shanghai Municipal Education Commission (D.L.), and the Shanghai Municipal Science and Technology Major Project (2019SHZDZX02 to C.L.).

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Correspondence to Dan Li or Cong Liu.

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Li, D., Liu, C. Hierarchical chemical determination of amyloid polymorphs in neurodegenerative disease. Nat Chem Biol 17, 237–245 (2021).

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