Dynamics of the Intrinsically Disordered α-Synuclein Protein in Monomer, Oligomer, and Fibril Forms Under Controlled Confinement

α-Synuclein (α-Syn) is an intrinsically disordered protein (IDP) in its monomeric form, that adopts oligomeric and fibrillar forms, with a β-sheet core structure, formed by the non-amyloid component (residues 61-95), flanked by intrinsically disordered regions (IDRs) in the N- (1-60) and C- (96-140) terminal domains. The function of monomeric α-syn remains ill-defined, while dysfunction is associated with aggregate forms in Parkinson's disease (PD). To determine molecular mechanistic aspects of α-syn function and dysfunction, temperature-controlled ice-boundary confinement in a frozen solution system is used to characterize the protein-coupled solvent dynamics for each α-syn form, by using spin-probe electron paramagnetic resonance spectroscopy. Comparison of α-syn in monomeric, oligomeric and fibrillar forms with soluble folded globular proteins reveals two major differences: (1) enhanced fluidity of the α-syn-coupled solvent, and (2) compressibility, which arises from the IDR components. Oligomer and fibril forms are distinguished by thermal hysteresis in phase dynamics and volumes. The results lead to a model, quantified by Arrhenius and van't Hoff analysis, in which the IDRs create a high-fluidity protein-coupled solvent phase with dynamics that persist as the phase volume is decreased by confinement compaction. The model provides insight into molecular mechanisms of α-syn function and dysfunction in the crowded neuron presynaptic region.