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

Amyloid aggregation of alpha -synuclein (alpha -syn) is closely associated with Parkinson's disease (PD) and other synucleinopathies. Several single amino-acid mutations (e.g. E46K) of alpha -syn have been identified causative to the early onset of familial PD. Here, we report the cryo-EM structure of an alpha -syn fibril formed by N-terminally acetylated E46K mutant alpha -syn (Ac-E46K). The fibril structure represents a distinct fold of alpha -syn, which demonstrates that the E46K mutation breaks the electrostatic interactions in the wild type (WT) alpha -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 alpha -syn and highlights the importance of electrostatic interactions in defining the fibril polymorphs. The E46K alpha -synuclein mutation causes familial Parkinson's disease. Here, the authors present the cryo-EM structure of N-terminally acetylated E46K alpha -synuclein fibrils and find that it is distinct from other known alpha -synuclein fibril structures.