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alpha-Synuclein has been centrally implicated in neurodegenerative disease, and a normal function in developmental synaptic plasticity has been suggested by studies in songbirds. A variety of observations suggest the protein partitions between membrane and cytosol, a behavior apparently conferred by a conserved structural similarity to the exchangeable apolipoproteins. Here we show that the capacity to bind lipids is broadly distributed across exons 3, 4, and 5 (encoding residues 1-102). Binding to phosphatidylserine-containing vesicles requires the presence of all three exons, while binding to phosphatidic acid can be mediated by any one of the three. Consistent with a "class A2" helical binding mechanism, lipid association is disrupted by introduction of charged residues along the hydrophobic face of the predicted alpha-helix and also by biotinylation of conserved lysines (which line the interfacial region). Circular dichroism spectroscopy reveals a general correlation between the amount of lipid-induced alpha-helix content and the degree of binding to PS-containing vesicles. Two point mutations associated with Parkinson's disease have little (A30P) or no (A53T) effect on lipid binding or alpha-helicity. These results are consistent with the hypothesis that alpha-synuclein's normal functions depend on an ability to undergo a large conformational change in the presence of specific phospholipids.

Synucleins are small highly conserved proteins in vertebrates, especially abundant in neurons and typically enriched at presynaptic terminals. Three genes in humans produce closely related synuclein proteins, all of which share a large amphipathic domain capable of reversible binding to lipid vesicles. Alpha synuclein has been specifically implicated in neurodegenerative disease. Two point mutations are genetically linked to familial Parkinson's disease, and alpha synuclein appears to form the major fibrillary component of Lewy bodies. Alpha synuclein also contributes to the intracellular inclusions of multiple system atrophy, and a fragment has been found in senile plaques in Alzheimer's disease. Although their normal cellular functions are unknown, several observations suggest the synucleins may serve to integrate presynaptic signaling and membrane trafficking. Alpha synuclein has been identified as a potent and selective inhibitor of phospholipase D2, which produces phosphatidic acid (to which synuclein binds) and is believed to function in the partitioning of membranes between the cell surface and intracellular stores. We outline a hypothesis whereby synuclein supports localized, experience-dependent turnover of synaptic membranes. Such a process may be important for lifelong learning and memory functions and may be especially vulnerable to disruption in aging-associated neurodegenerative diseases.