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

Author

Listed:
  • Kun Zhao

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Yaowang Li

    (Tsinghua University)

  • Zhenying Liu

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Houfang Long

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Chunyu Zhao

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Feng Luo

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Yunpeng Sun

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Youqi Tao

    (Shanghai Jiao Tong University)

  • Xiao-dong Su

    (Peking University)

  • Dan Li

    (Shanghai Jiao Tong University
    Shanghai Jiao Tong University)

  • Xueming Li

    (Tsinghua University)

  • Cong Liu

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

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.

Suggested Citation

  • Kun Zhao & Yaowang Li & Zhenying Liu & Houfang Long & Chunyu Zhao & Feng Luo & Yunpeng Sun & Youqi Tao & Xiao-dong Su & Dan Li & Xueming Li & Cong Liu, 2020. "Parkinson’s disease associated mutation E46K of α-synuclein triggers the formation of a distinct fibril structure," Nature Communications, Nature, vol. 11(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16386-3
    DOI: 10.1038/s41467-020-16386-3
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    Cited by:

    1. Dhruva D. Dhavale & Alexander M. Barclay & Collin G. Borcik & Katherine Basore & Deborah A. Berthold & Isabelle R. Gordon & Jialu Liu & Moses H. Milchberg & Jennifer Y. O’Shea & Michael J. Rau & Zacha, 2024. "Structure of alpha-synuclein fibrils derived from human Lewy body dementia tissue," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    2. Youqi Tao & Yunpeng Sun & Shiran Lv & Wencheng Xia & Kun Zhao & Qianhui Xu & Qinyue Zhao & Lin He & Weidong Le & Yong Wang & Cong Liu & Dan Li, 2022. "Heparin induces α-synuclein to form new fibril polymorphs with attenuated neuropathology," Nature Communications, Nature, vol. 13(1), pages 1-9, December.

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