Synucleins in synaptic plasticity and neurodegenerative disorders

Synucleins are small highly conserved proteins in vertebrates, especially a bundant in neurons and typically enriched at presynaptic terminals. Three g enes in humans produce closely related synuclein proteins, all of which sha re a large amphipathic domain capable of reversible binding to lipid vesicl es. Alpha synuclein has been specifically implicated in neurodegenerative d isease. 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 incl usions of multiple system atrophy, and a fragment has been found in senile plaques in Alzheimer's disease. Although their normal cellular functions ar e unknown, several observations suggest the synucleins may serve to integra te 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 fu nction in the partitioning of membranes between the cell surface and intrac ellular stores. We outline a hypothesis whereby synuclein supports localize d. experience-dependent turnover of synaptic membranes. Such a process may be important for lifelong learning and memory functions and may be especial ly vulnerable to disruption in aging-associated neurodegenerative diseases. (C) 1999 Wiley-Liss, Inc.