Morphological Evaluation of Meta-stable Oligomers of ?-Synuclein with Small-Angle Neutron Scattering.

ABSTRACT: Amyloidogenesis of ?-synuclein (?S) is considered to be a pathological phenomenon related to Parkinson's disease (PD). As a key component to reveal the fibrillation mechanism and toxicity, we have investigated an oligomeric species of ?S capable of exhibiting the unit-assembly process leading to accelerated amyloid fibril formation. These oligomers previously shown to exist in a meta-stable state with mostly disordered structure and unable to seed the fibrillation were converted to either temperature-sensitive self-associative oligomers or NaCl-induced non-fibrillating oligomeric species. Despite their transient and disordered nature, the structural information of meta-stable ?S oligomers (Meta-?S-Os) was successfully evaluated with small-angle neutron scattering (SANS) technique. By fitting the neutron scattering data with polydisperse Gaussian Coil (pGC) model, Meta-?S-O was analyzed as a sphere with approximate diameter of 100?Å. Its overall shape altered drastically with subtle changes in temperature between 37?°C and 43?°C, which would be responsible for fibrillar polymorphism. Based on their bifurcating property of Meta-?S-Os leading to either on-pathway or off-pathway species, the oligomers could be suggested as a crucial intermediate responsible for the oligomeric diversification and multiple fibrillation processes. Therefore, Meta-?S-Os could be considered as a principal target to control the amyloidogenesis and its pathogenesis.

SUBMITTER: Bhak G 

PROVIDER: S-EPMC6155208 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature