Membrane interactions and fibrillization of α-synuclein play an essential role in membrane disruption

• Membrane damage caused by α-synuclein aggregation is mediated by fibril growth and lipid extraction.
• Binding of α-synuclein is required for fibrillization-induced membrane damage.
• In contrast to oligomer-induced damage, strong binding is not necessary, and membranes with only 30% charged lipids are also vulnerable.
• Aggregation of α-synuclein in the presence of vesicles results in complete membrane disruption and the formation Lewy bodies like aggregates.

We studied α-synuclein (αS) aggregation in giant vesicles, and observed dramatic membrane disintegration, as well as lipid incorporation into micrometer-sized suprafibrillar aggregates. In the presence of dye-filled vesicles, dye leakage and fibrillization happen concurrently. However, growing fibrils do not impair the integrity of phospholipid vesicles that have a low affinity for αS. Seeding αS aggregation accelerates dye leakage, indicating that oligomeric species are not required to explain the observed effect. The evolving picture suggests that fibrils that appear in solution bind membranes and recruit membrane-bound monomers, resulting in lipid extraction, membrane destabilization and the formation of lipid-containing suprafibrillar aggregates.