Abstract
α-Synuclein (α-syn) amyloid fibrils are the major component of Lewy bodies, which are the pathological hallmark of Parkinson’s disease (PD) and other synucleinopathies. High-resolution structure of α-syn fibril is important for understanding its assembly and pathological mechanism. Here, we determined a fibril structure of full-length α-syn (1–140) at the resolution of 3.07 Å by cryo-electron microscopy (cryo-EM). The fibrils are cytotoxic, and transmissible to induce endogenous α-syn aggregation in primary neurons. Based on the reconstructed cryo-EM density map, we were able to unambiguously build the fibril structure comprising residues 37–99. The α-syn amyloid fibril structure shows two protofilaments intertwining along an approximate 21 screw axis into a left-handed helix. Each protofilament features a Greek key-like topology. Remarkably, five out of the six early-onset PD familial mutations are located at the dimer interface of the fibril (H50Q, G51D, and A53T/E) or involved in the stabilization of the protofilament (E46K). Furthermore, these PD mutations lead to the formation of fibrils with polymorphic structures distinct from that of the wild-type. Our study provides molecular insight into the fibrillar assembly of α-syn at the atomic level and sheds light on the molecular pathogenesis caused by familial PD mutations of α-syn.
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Acknowledgements
This work was supported by the Major State Basic Research Development Program (2016YFA0501902 to C.L., X.L. and 2016YFA0501102 to X.L.), the National Natural Science Foundation (NSF) of China (31470748 to C.L. and 31570730 and 31722015 to X.L.), the Chinese Academy of Sciences (to C.L.), The “1000 Talents Plan” of China to C.L. and X.L., the Advanced Innovation Center for Structural Biology (to X.L.), Tsinghua-Peking Joint Center for Life Sciences (to X.L.), Shanghai Pujiang Program (to D.L.). We acknowledge Tsinghua University Branch of China National Center for Protein Sciences Beijing for providing facility supports in cryo-EM.
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X.L., C.L., D.L., Y.L. and C.Z. designed the project. Y.L. and F.L. performed the cryo-electron microscopy experiments. Y.L. and Z.Luo built and refined the structure model. C.Z., X.G. and X.Z. performed the biochemical and cellular assays. Z.Liu performed the AFM experiments. Y.L., C.Z., D.L., X.L. and C.L. analyzed the data and contributed to manuscript discussion and editing. D.L. and X.L. wrote the manuscript.
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Li, Y., Zhao, C., Luo, F. et al. Amyloid fibril structure of α-synuclein determined by cryo-electron microscopy. Cell Res 28, 897–903 (2018). https://doi.org/10.1038/s41422-018-0075-x
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DOI: https://doi.org/10.1038/s41422-018-0075-x
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