Oligomeric and Fibrillar α-Synuclein Display Persistent Dynamics and Compressibility under Controlled Confinement.

Area of Science:

• Neuroscience
• Biochemistry
• Structural Biology

Background:

• Alpha-synuclein's role in neurotransmitter release and Parkinson's disease remains incompletely understood.
• Investigating the molecular mechanisms of alpha-synuclein function and dysfunction is critical.

Purpose of the Study:

• To explore the coupled protein and solvent dynamics of alpha-synuclein oligomers and fibrils.
• To gain insights into the molecular properties underlying alpha-synuclein's function and dysfunction.

Main Methods:

• Utilized a low-temperature system to control confinement and electron paramagnetic resonance (EPR) spin probe localization.
• Examined the rotational mobility of the spin probe in solvent-protein regions of alpha-synuclein oligomers and fibrils.

Main Results:

• Identified two distinct alpha-synuclein-associated solvent components with higher fluidities than globular proteins, resembling aqueous-cryosolvent mesophases.
• Observed a temperature-dependent decrease in the volume of the high-fluidity mesophase for alpha-synuclein oligomers and fibrils, indicating compressibility.
• Detected thermal hysteresis in mobilities and component weights.

Conclusions:

• Proposed a model where the disordered C-terminal domain of alpha-synuclein forms a compressible, fluid phase under confinement.
• Concluded that robust dynamics and compressibility are fundamental properties of alpha-synuclein oligomers and fibrils.
• Suggested these properties may contribute to alpha-synuclein dysfunction and inform its normal function.