α-Synuclein Early-Oligomers Regulate Self-Assembly through Nucleation and Liquid-Liquid Phase Separation.

Area of Science:

• Biochemistry
• Neuroscience
• Molecular Biology

Background:

• Lewy body formation from alpha-synuclein (α-syn) aggregation is central to Parkinson's disease pathogenesis.
• α-Syn aggregation involves liquid-liquid phase separation (LLPS) and liquid-to-solid phase transitions (LSPT).

Purpose of the Study:

• To reconstitute an instantaneous LLPS system for α-syn.
• To investigate the structural and kinetic aspects of early-stage α-syn aggregation within the dense phase.

Main Methods:

• Reconstitution of an instantaneous α-syn liquid-liquid phase separation (LLPS) system.
• Characterization of early-stage oligomers formed within the LLPS dense phase, focusing on electrostatic interactions.

Main Results:

• LLPS accelerates α-syn aggregation through nucleation and oligomerization.
• Early-stage oligomers are hollow spheres with a loosely packed β-turn conformation within liquid-like droplets.
• Liquid-to-solid phase transition (LSPT) of condensates contributes to amyloid deposition.

Conclusions:

• The study elucidates the role of LLPS in α-syn self-assembly and early oligomerization.
• Findings provide insights into the molecular mechanisms of α-syn aggregation kinetics in Parkinson's disease.
• Understanding these processes may inform the development of novel therapeutic strategies.