α‐Synuclein–synaptosomal membrane interactions

α-Synuclein exists in two different compartments in vivo– correspondingly existing as two different forms: a membrane-bound form that is predominantly α-helical and a cytosolic form that is randomly structured. It has been suggested that these environmental and structural differences may play a role in aggregation propensity and development of pathological lesions observed in Parkinson's disease (PD). Such effects may be accentuated by mutations observed in familial PD kindreds. In order to test this hypothesis, wild-type and A53T mutant α-synuclein interactions with rat brain synaptosomal membranes were examined. Previous data has demonstrated that the A30P mutant has defective lipid binding and therefore was not examined in this study. Electron microscopy demonstrated that wild-type α-synuclein fibrillogenesis is accelerated in the presence of synaptosomal membranes whereas the A53T α-synuclein fibrillogenesis is inhibited under the same conditions. These results suggested that subtle sequence changes in α-synuclein could significantly alter interaction with membrane bilayers. Fluorescence and absorption spectroscopy using environment sensitive probes demonstrated variations in the inherent lipid properties in the presence and absence of α-synuclein. Addition of wild-type α-synuclein to synaptosomes did not significantly alter the membrane fluidity at either the fatty acyl chains or headgroup space, suggesting that synaptosomes have a high capacity for α-synuclein binding. In contrast, synaptosomal membrane fluidity was decreased by A53T α-synuclein binding with concomitant packing of the lipid headgroups. These results suggest that alterations in α-synuclein–lipid interactions may contribute to physiological changes detected in early onset PD.