Interactions between fatty acids and α-synuclein

alpha-Synuclein (alpha S) is an amyloidogenic neuronal protein associated with several neurodegenerative disorders. Although unstructured in solution, alpha S forms a-helices in the presence of negatively charged lipid surfaces. Moreover, alpha S was shown to interact with FAs in a manner that promotes protein aggregation. Here, we investigate whether S has specific FA binding site(s) similar to fatty acid binding proteins (FABPs), such as the intracellular FABPs. Our NMR experiments reveal that FA addition results in i) the simultaneous loss of aS signal in both H-1 and C-13 spectra and ii) the appearance of a very broad FA C-13-carboxyl signal. These data exclude high-affinity binding of FA molecules to specific aS sites, as in FABPs. One possible mode of binding was revealed by electron microscopy studies of oleic acid bilayers at pH 7.8; these high-molecular-weight FA aggregates possess a net negative surface charge because they contain FA anions, and they were easily disrupted to form smaller particles in the presence of aS, indicating a direct protein-lipid interaction. We conclude that alpha S is not likely to act as an intracellular FA carrier. Binding to negatively charged membranes, however, appears to be an intrinsic property of aS that is most likely related to its physiological role (s) in the cell.