Membrane lipid co-aggregation with α-synuclein fibrils

Area of Science:

• Biochemistry
• Neuroscience
• Materials Science

Background:

• Amyloid deposits in human diseases often contain membrane lipids.
• Lipid-protein co-aggregation influences the structure and function of both membranes and amyloid deposits.
• The mechanisms and molecular structures of lipid-amyloid co-aggregation remain poorly understood.

Purpose of the Study:

• To investigate the in vitro co-aggregation mechanism between phospholipid model membranes and alpha-synuclein.
• To elucidate the molecular structure and dynamics of lipid-protein co-aggregates.

Main Methods:

• Incubation of monomeric alpha-synuclein with anionic phospholipid model membranes.
• Phospholipid quantification.
• Solid-state NMR with polarization transfer.
• Cryo-transmission electron microscopy (cryo-TEM).

Main Results:

• Spontaneous uptake of phospholipids into alpha-synuclein amyloid fibrils.
• Evidence of saturable co-aggregation dependent on lipid composition.
• At low lipid-protein ratios, phospholipids closely associate with fibrils, reducing mobility and altering morphology.
• At higher ratios, vesicles adsorb to fibrils.

Conclusions:

• Amyloid formation in the presence of lipids is a co-aggregation process.
• Lipid-protein co-aggregates exhibit unique structures, dynamics, and morphologies compared to individual components.
• Findings offer new perspectives on amyloid pathology and lipid-protein interactions.