Parkinson’s disease associated mutation E46K of α-synuclein triggers the formation of a distinct fibril structure

Kun Zhao, Yaowang Li, Zhenying Liu, Houfang Long, Chunyu Zhao, Feng Luo, Yunpeng Sun, Youqi Tao, Xiao-dong Su, Dan Li (), Xueming Li () and Cong Liu ()
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Kun Zhao: Chinese Academy of Sciences
Yaowang Li: Tsinghua University
Zhenying Liu: Chinese Academy of Sciences
Houfang Long: Chinese Academy of Sciences
Chunyu Zhao: Chinese Academy of Sciences
Feng Luo: Chinese Academy of Sciences
Yunpeng Sun: Chinese Academy of Sciences
Youqi Tao: Shanghai Jiao Tong University
Xiao-dong Su: Peking University
Dan Li: Shanghai Jiao Tong University
Xueming Li: Tsinghua University
Cong Liu: Chinese Academy of Sciences

Nature Communications, 2020, vol. 11, issue 1, 1-9

Abstract: Abstract Amyloid aggregation of α-synuclein (α-syn) is closely associated with Parkinson’s disease (PD) and other synucleinopathies. Several single amino-acid mutations (e.g. E46K) of α-syn have been identified causative to the early onset of familial PD. Here, we report the cryo-EM structure of an α-syn fibril formed by N-terminally acetylated E46K mutant α-syn (Ac-E46K). The fibril structure represents a distinct fold of α-syn, which demonstrates that the E46K mutation breaks the electrostatic interactions in the wild type (WT) α-syn fibril and thus triggers the rearrangement of the overall structure. Furthermore, we show that the Ac-E46K fibril is less resistant to harsh conditions and protease cleavage, and more prone to be fragmented with an enhanced seeding capability than that of the WT fibril. Our work provides a structural view to the severe pathology of the PD familial mutation E46K of α-syn and highlights the importance of electrostatic interactions in defining the fibril polymorphs.

Date: 2020
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DOI: 10.1038/s41467-020-16386-3

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