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

Abstract

-Synuclein (-syn) amyloid fibril, as the major component of Lewy bodies and pathological entity spreading in human brain, is closely associated with Parkinsons disease (PD) and other synucleinopathies. Several single amino-acid mutations (e.g. E46K) of -syn have been identified causative to the early onset of familial PD. Here, we determined the cryo-EM structure of a full-length -syn fibril formed by N-terminal acetylated E46K mutant -syn (Ac-E46K). The fibril structure represents a new fold of -syn, which demonstrates that the E46K mutation breaks the electrostatic interactions in the wild type (WT) -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 a higher capability of seeding fibril formation than that of the WT fibril. Our work provides a structural view to the severe pathology of the PD familial mutation E46K of -syn and highlights the importance of electrostatic interactions in defining the fibril polymorphs.