Amyloid fibril structure of α-synuclein determined by cryo-electron microscopy

摘要

α-Synuclein (α-syn) amyloid fibrils are the major component of Lewy bodies,which are the pathological hallmark of Parkinson's disease (PD) and other synucleinopathies.High-resolution structure of α-syn fibril is important for understanding its assembly and pathological mechanism.Here,we determined a fibril structure of full-length α-syn (1-140) at the resolution of 3.07 (A) by cryo-electron microscopy (cryo-EM).The fibrils are cytotoxic,and transmissible to induce endogenous α-syn aggregation in primary neurons.Based on the reconstructed cryo-EM density map,we were able to unambiguously build the fibril structure comprising residues 37-99.The α-syn amyloid fibril structure shows two protofilaments intertwining along an approximate 21 screw axis into a left-handed helix.Each protofilament features a Greek key-like topology.Remarkably,five out of the six early-onset PD familial mutations are located at the dimer interface of the fibril (H50Q,G51D,and A53T/E) or involved in the stabilization of the protofilament (E46K).Furthermore,these PD mutations lead to the formation of fibrils with polymorphic structures distinct from that of the wild-type.Our study provides molecular insight into the fibrillar assembly of α-syn at the atomic level and sheds light on the molecular pathogenesis caused by familial PD mutations of α-syn.