Lipid binding inhibits α-synuclein fibril formation

Abstract

Parkinson's disease is the second most common neurodegenerative disorder, and the cause is unknown; however, substantial evidence implicates the aggregation of α-synuclein as a critical factor in the etiology of the disease. α-Synuclein is a relatively abundant brain protein of unknown function, and the purified protein is intrinsically unfolded. The amino acid sequence has seven repeats with an apolipoprotein lipid-binding motif, which are predicted to form amphiphilic helices. We have investigated the interaction of α-synuclein with lipid vesicles of different sizes and properties by monitoring the effects on the conformation of the protein and the kinetics of fibrillation. The nature of the interaction of α-synuclein with vesicles was highly dependent on the phospholipid composition, the ratio of α-synuclein to phospholipid, and the size of the vesicles. The strongest interactions were between α-synuclein and vesicles composed of 1,2-dipalmitoyl-sn-glycero-3-phosphate/1,2-dipalmitoyl-sn-glycero-3- phosphocholine and 1,2-dipalmitoyl-sn-glycero-3-phospho-RAC-(1-glycerol)/1,2-dipalmitoyl-sn- glycero-3-phosphocholine and involved formation of helical structure in α-synuclein. A strong correlation was observed between the induction of α-helix in α-synuclein and the inhibition of fibril formation. Thus, helical, membrane-bound α-synuclein is unlikely to contribute to aggregation and fibrillation. Given that a significant fraction of α-synuclein is membrane-bound in dopaminergic neurons, this observation has significant physiological significance.