Conformational Switch in the Alpha-Synuclein C-Terminal Domain Directs Its Fibril Polymorphs.

ABSTRACT: α-Synuclein (αSyn) 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 remain unveiled. In this study, we found that fibril morphology is associated with the conformational state of monomeric αSyn. Through systematic evaluation of the ionic strength and temperature, we generated two distinct polymorphs: a twisted morphology at low ionic strength and temperature, and a rod-like morphology at higher ionic strength and temperature. Using solid-state NMR, we revealed that both polymorphs share a highly conserved core structure, with morphological differences arising probably from distinct structural arrang

SUBMITTER: Aguirre C 

PROVIDER: S-EPMC12223483 | biostudies-literature | 2025 May

REPOSITORIES: biostudies-literature