Amyloid fibril structure of ?-synuclein determined by cryo-electron microscopy.

ABSTRACT: ?-Synuclein (?-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 ?-syn fibril is important for understanding its assembly and pathological mechanism. Here, we determined a fibril structure of full-length ?-syn (1-140) at the resolution of 3.07?Å by cryo-electron microscopy (cryo-EM). The fibrils are cytotoxic, and transmissible to induce endogenous ?-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 ?-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 ?-syn at the atomic level and sheds light on the molecular pathogenesis caused by familial PD mutations of ?-syn.

SUBMITTER: Li Y 

PROVIDER: S-EPMC6123497 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature