β-Synuclein suppresses both the initiation and amplification steps of α-synuclein aggregation via competitive binding to surfaces

alpha-Synuclein is an intrinsically disordered protein that is associated with the pathogenesis of Parkinson's disease through the processes involved in the formation of amyloid fibrils. alpha and beta-synuclein are homologous proteins found at comparable levels in presynaptic terminals but beta-synuclein has a greatly reduced propensity to aggregate and indeed has been found to inhibit alpha-synuclein aggregation. In this paper, we describe how sequence differences between alpha- and beta- synuclein affect individual microscopic processes in amyloid formation. In particular, we show that beta-synuclein strongly suppresses both lipidinduced aggregation and secondary nucleation of alpha-synuclein by competing for binding sites at the surfaces of lipid vesicles and fibrils, respectively. These results suggest that beta-synuclein can act as a natural inhibitor of alpha-synuclein aggregation by reducing both the initiation of its self-assembly and the proliferation of its aggregates.