Interactions between fatty acids and α-synuclein

a-Synuclein (aS) is an amyloidogenic neuronal proteinassociatedwithseveralneurodegenerativedisorders. Although unstructured in solution, aS forms a-helices in the presence of negatively charged lipid surfaces. Moreover, aS was shown to interact with FAs in a manner that promotes protein aggregation. Here, we investigate whether aS 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 si- multaneous loss of aS signal in both 1 H and 13 C spectra and ii) the appearance of a very broad FA 13 C-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 bi- layers 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 aS 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.—Lucke, C., D. L. Gantz, E. Klimtchuk, and J. A. Hamilton. Interactions between fatty acids and a-synuclein. J. Lipid Res. 2006. 47: 1714-1724.