Abstract
Interactions of monomeric alpha-synuclein (alphaS) with lipid membranes have been suggested to play an important role in initiating aggregation of alphaS. We have systematically analyzed the distribution and self-assembly of monomeric alphaS on supported lipid bilayers. We observe that at protein/lipid ratios higher than 1:10, alphaS forms micrometer-sized clusters, leading to observable membrane defects and decrease in lateral diffusion of both lipids and proteins. An alphaS deletion mutant lacking amino-acid residues 71-82 binds to membranes, but does not observably affect membrane integrity. Although this deletion mutant cannot form amyloid, significant amyloid formation is observed in the wild-type alphaS clusters. These results suggest that the process of amyloid formation, rather than binding of alphaS on membranes, is crucial in compromising membrane integrity.
