Parkinson\u2019s disease associated mutation E46K of \u03b1-synuclein triggers the formation of a distinct fibril structure

Kun Zhao,Youqi Tao,Xiao-Dong Su,Feng Luo,Zhenying Liu,Chunyu Zhao,Yaowang Li,Houfang Long,Cong Liu,Yunpeng Sun,Xueming Li,Dan Li

doi:10.1038/s41467-020-16386-3

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.

Highlights

Amyloid aggregation of α-synuclein (α-syn) is closely associated with Parkinson’s disease (PD) and other synucleinopathies
The cryo-EM structure of full-length wild-type (WT) α-syn fibril demonstrates that in the five mutation sites found in familial PD, four of them, i.e. E46K, A53T/E, G51D, and H50Q, are located at the protofilamental interface of the wild type (WT) fibril[15,16], which indicates that these mutations may alter the fibril structure and influence α-syn amyloid aggregation and PD pathology
We further show that the acetylated E46K mutant α-syn (Ac-E46K) fibril is less stable than the WT fibril under harsh conditions and protease cleavage, while the mutant fibril is more efficient in seeding amyloid fibril formation

Summary

Introduction

Amyloid aggregation of α-synuclein (α-syn) is closely associated with Parkinson’s disease (PD) and other synucleinopathies. 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. The cryo-EM structure of full-length wild-type (WT) α-syn fibril demonstrates that in the five mutation sites found in familial PD, four of them, i.e. E46K, A53T/E, G51D, and H50Q, are located at the protofilamental interface of the WT fibril[15,16], which indicates that these mutations may alter the fibril structure and influence α-syn amyloid aggregation and PD pathology. This work provides a structural mechanism for the influence of E46K on the amyloid fibril formation of α-syn, and suggests that electrostatic interactions may serve as one of the driving force for the polymorphic fibril formation of α-syn

Methods

Results

Conclusion