The association of α-synuclein with membranes affects bilayer structure, stability, and fibril formation

Abstract

The aggregation of α-synuclein is believed to be a critical factor in the etiology of Parkinson's disease. α-Synuclein is an abundant neuronal protein of unknown function, which is enriched in the presynaptic terminals of neurons. Although α-synuclein is found predominantly in the cytosolic fractions, membrane-bound α-synuclein has been suggested to play an important role in fibril formation. The effects of α-synuclein on lipid bilayers of different compositions were determined using fluorescent environment-specific probes located at various depths. α -Synuclein-membrane interactions were found to affect both protein and membrane properties. Our results indicate that in addition to electrostatic interactions, hydrophobic interactions are important in the association of the protein with the bilayer, and lead to disruption of the membrane. The latter was observed by atomic force microscopy and fluorescent dye leakage from vesicles. The kinetics of α-synuclein fibril formation were significantly affected by the protein association and subsequent membrane disruption, and reflected the conformation of α-synuclein. The ability of α-synuclein to disrupt membranes correlated with the binding affinity of α-synuclein for the particular membrane composition, and to the induced helical conformation of α-synuclein. Protofibrillar or fibrillar α-synuclein. caused a much more rapid destruction of the membrane than soluble monomeric α-synuclein, indicating that protofibrils (oligomers) or fibrils are likely to be significantly neurotoxic.