Kawata, Y. | Search bioRxiv

bioRxiv2022

Conformational change in the monomeric alpha-synuclein imparts fibril polymorphs

-Synuclein (Syn) inclusions are a pathological hallmark of several neurodegenerative disorders. While cryo-electron microscopy studies have revealed distinct fibril polymorphs across different synucleinopathies, the molecular switches controlling polymorphism remained unveiled. In this study, we found that fibril morphology is associated with the conformational state of monomeric Syn. Through systematic manipulation of the ionic strength and temperature, we pinpoint two distinct polymorphs: a twisted morphology at low ionic strength and temperature, and a rod-like morphology at higher ionic strength and temperature. Most strikingly, we found that a specific conformational change in the C-terminal domain of the monomeric Syn serves as the master switch for the formation of polymorphs. Interestingly, this conformational change can be triggered by calcium binding to the C-terminus, connecting environmental factors to specific fibril architectures. Our results unmask the C-terminal domain as a key player for orchestrating Syn fibril morphology, providing significant insights into the fibrogenesis of Syn. Significance StatementThe Syn C-terminus domain acts as the master switch programming its fibril polymorphism.

biophysics↗

bioRxiv2021

Dual effects of presynaptic membrane mimetics on α-synuclein amyloid aggregation

Aggregation of intrinsically disordered -synuclein (SN) under various conditions is closely related to synucleinopathies. Although various biological membranes have shown to alter the structure and aggregation propensity of SN, a thorough understanding of the molecular and mechanical mechanism of amyloidogenesis in membranes remains unanswered. Herein, we examined the structural changes, binding properties, and amyloidogenicity of three variations of SN mutants under two types of liposomes, 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) and presynaptic vesicle mimetic (Mimic) membranes. While neutrally charged DOPC membranes elicited marginal changes in the structure and amyloid fibrillation of SNs, negatively charged Mimic membranes induced dramatic helical folding and biphasic amyloid generation. At low concentration of Mimic membranes, the amyloid fibrillation of SNs was promoted in a dose-dependent manner. However, further increases in the concentration constrained the fibrillation process. These results suggest the dual effect of Mimic membranes on regulating the amyloidogenesis of SN, which is rationalized by the amyloidogenic structure of SN and condensation-dilution of local SN concentration. Finally, we propose physicochemical properties of SN and membrane surfaces, and their propensity to drive electrostatic interactions as decisive factors of amyloidogenesis.

biophysics↗