Selective effects of alpha-synuclein on membrane phospholipids and mitochondrial function

α-Synuclein (αSyn) is a small cytosolic protein that is highly enriched in neurons, particularly at presynaptic terminals, and has been implicated in the pathogenesis of Parkinson's disease (PD). Missense mutations or multiplication of the gene encoding αSyn cause early-onset autosomal dominant familial PD, and Lewy bodies and Lewy neurites, the neuropathological hallmarks of both sporadic and familial PD, contain insoluble aggregates of αSyn. Despite decades of intensive study, the precise pathophysiological function of αSyn remains unknown. It has been proposed to function in lipid binding, regulation of membrane phospholipid composition, regulation of neurotransmitter release and/or of the reserve pool of synaptic vesicles, and in effects on mitochondrial function. In order to help clarify the role of αSyn in PD pathogenesis, my research has focused on the normal function of this protein within neurons and neuronal cells. My first project sought to extend published findings on the reported function of αSyn as an inhibitor of phospholipase D. However, my results conclusively showed that αSyn does not inhibit phospholipase D in several systems and conditions. My second project used an unbiased lipidomics analysis to investigate whether αSyn expression affects phospholipid composition in mouse brain. We identified age-dependent effects of αSyn gene dosage, but our most striking findings shed light on the lipid biochemistry of the aging (wild-type) brain. My third project examines the effects of αSyn on selected aspects of mitochondrial function. I show that αSyn increases regulated cytochrome c release from isolated mitochondria and may increase the total pool of cytochrome c, and that αSyn expression affects mitochondrial membrane potential and sensitivity to toxins. Thus, my research has helped to narrow the list of possible functions of αSyn and suggests novel approaches to PD therapeutics.