Distinct α-Synuclein:Lipid Co-Structure Complexes Affect Amyloid Nucleation through Fibril Mimetic Behavior

Area of Science:

• Biochemistry and Biophysics
• Neuroscience
• Structural Biology

Background:

• Parkinson's disease (PD) is characterized by Lewy bodies, aggregates of lipids and fibrillated alpha-synuclein (aSN).
• Alpha-synuclein (aSN) is an intrinsically disordered protein with physiological roles involving interactions with lipids.
• Lipid-protein assemblies, termed co-structures, represent a specific state of aSN interacting with lipids.

Purpose of the Study:

• To investigate the formation kinetics and mechanism of alpha-synuclein:lipid co-structures.
• To determine the stoichiometry of aSN:lipid co-structure formation.
• To assess the impact of aSN:lipid co-structures on alpha-synuclein fibril nucleation.

Main Methods:

• Kinetic analysis of alpha-synuclein:lipid co-structure formation.
• Seeded fibrillation assays to evaluate fibril nucleation.
• Small-angle X-ray scattering (SAXS) to model co-structure formation on lipid vesicles.

Main Results:

• Alpha-synuclein:lipid co-structures form with a specific stoichiometry.
• These co-structures significantly accelerate alpha-synuclein fibril nucleation compared to lipid vesicles alone.
• A SAXS-based model indicates aSN decorates lipid vesicle surfaces, mimicking fibril surfaces and promoting nucleation.

Conclusions:

• Alpha-synuclein:lipid co-structures play a critical role in accelerating alpha-synuclein fibril formation.
• The surface properties of these co-structures enhance fibril nucleation.
• The balance of aSN structural states near membranes may dictate functional versus pathological outcomes.