May 28, 2020

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

Nature Communications
Kun ZhaoCong Liu

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.

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Mentioned in this Paper

Mutant
Parkinson Disease
Gene Rearrangement
EMILIN1 wt Allele
Fibril - Cell Component
Structure
Proteolysis
Peptide Hydrolases
Azacitidine
Alpha-Synuclein

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