Synucleins in synaptic plasticity and neurodegenerative disorders

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.