The hereditary mutation G51D unlocks a distinct fibril strain transmissible to wild-type α-synuclein

Yunpeng Sun, Houfang Long, Wencheng Xia, Kun Wang, Xia Zhang, Bo Sun, Qin Cao, Yaoyang Zhang, Bin Dai, Dan Li and Cong Liu ()
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Yunpeng Sun: Chinese Academy of Sciences
Houfang Long: Chinese Academy of Sciences
Wencheng Xia: Chinese Academy of Sciences
Kun Wang: Chinese Academy of Sciences
Xia Zhang: ShanghaiTech University
Bo Sun: ShanghaiTech University
Qin Cao: Shanghai Jiao Tong University
Yaoyang Zhang: Chinese Academy of Sciences
Bin Dai: Shanghai Jiao Tong University
Dan Li: Shanghai Jiao Tong University
Cong Liu: Chinese Academy of Sciences

Nature Communications, 2021, vol. 12, issue 1, 1-10

Abstract: Abstract α-Synuclein (α-Syn) can form different fibril strains with distinct polymorphs and neuropathologies, which is associated with the clinicopathological variability in synucleinopathies. How different α-syn fibril strains are produced and selected under disease conditions remains poorly understood. In this study, we show that the hereditary mutation G51D induces α-syn to form a distinct fibril strain in vitro. The cryogenic electron microscopy (cryo-EM) structure of the G51D fibril strain was determined at 2.96 Å resolution. The G51D fibril displays a relatively small and extended serpentine fold distinct from other α-syn fibril structures. Moreover, we show by cryo-EM that wild-type (WT) α-syn can assembly into the G51D fibril strain via cross-seeding with G51D fibrils. Our study reveals a distinct structure of G51D fibril strain triggered by G51D mutation but feasibly adopted by both WT and G51D α-syn, which suggests the cross-seeding and strain selection of WT and mutant α-syn in familial Parkinson’s disease (fPD).

Date: 2021
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DOI: 10.1038/s41467-021-26433-2

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