Lipid-induced polymorphic amyloid fibril formation by α-synuclein

Area of Science:

• Biochemistry
• Neuroscience
• Materials Science

Background:

• Proteins self-assemble into amyloid fibers, which can exist in diverse polymorphic forms.
• Amyloid polymorphs exhibit varying toxicity and are linked to different disease conditions.
• Factors driving amyloid fibril polymorphism remain largely unknown.

Purpose of the Study:

• To investigate the role of lipid membranes in alpha-synuclein amyloid aggregation.
• To determine if lipid interfaces influence the diversity of amyloid fibril morphologies.
• To explore the incorporation of lipids into alpha-synuclein fibrils.

Main Methods:

• Utilized 1,2-dimyristoyl-sn-glycero-3-phospho-L-serine (a neuronal plasma membrane lipid) in alpha-synuclein aggregation experiments.
• Analyzed the morphological diversity of resulting amyloid fibrils using high-resolution imaging techniques.
• Confirmed lipid incorporation into the formed amyloid structures.

Main Results:

• The presence of the lipid markedly accelerated alpha-synuclein aggregation.
• A wide range of polymorphic forms, including fibrils, ribbons, nanotubes, and sheets, were generated under identical conditions.
• Amyloid fibrils were found to incorporate lipid molecules into their structures.
• Lipid interfaces were shown to modulate aggregation kinetics and induce morphological variations.

Conclusions:

• Lipid membranes can significantly accelerate alpha-synuclein amyloid aggregation.
• Membrane interfaces play a crucial role in generating diverse amyloid fibril polymorphs.
• Lipid incorporation into fibrils suggests a mechanism for altered fibril properties and potential disease relevance, as seen in Lewy bodies.