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

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.

journal_name

Nat Commun

journal_title

Nature communications

authors

Zhao K,Li Y,Liu Z,Long H,Zhao C,Luo F,Sun Y,Tao Y,Su XD,Li D,Li X,Liu C

doi

10.1038/s41467-020-16386-3

subject

Has Abstract

pub_date

2020-05-26 00:00:00

pages

2643

issue

1

issn

2041-1723

pii

10.1038/s41467-020-16386-3

journal_volume

11

pub_type

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