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

• Published in: Scientific reports Vol. 6; no. 1; p. 36010
• Main Authors: Brown, James W. P., Buell, Alexander K., Michaels, Thomas C. T., Meisl, Georg, Carozza, Jacqueline, Flagmeier, Patrick, Vendruscolo, Michele, Knowles, Tuomas P. J., Dobson, Christopher M., Galvagnion, Céline
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03.11.2016; Nature Publishing Group
• Subjects: 631/57/2269; 639/638/45/287/1194; 639/638/92/612/1237; 692/699/375; 82/58; 82/62; 82/80; 82/83; alpha-Synuclein - chemistry; alpha-Synuclein - metabolism; Amino Acid Sequence; beta-Synuclein - chemistry; beta-Synuclein - metabolism; Binding, Competitive; Humanities and Social Sciences; Hydrogen-Ion Concentration; Lipids - chemistry; multidisciplinary; Phosphatidylserines - chemistry; Protein Aggregates; Protein Aggregation, Pathological; Protein Binding; Science; Sequence Alignment; Surface Properties
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep36010

α -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. α and β -synuclein are homologous proteins found at comparable levels in presynaptic terminals but β -synuclein has a greatly reduced propensity to aggregate and indeed has been found to inhibit α -synuclein aggregation. In this paper, we describe how sequence differences between α - and β -synuclein affect individual microscopic processes in amyloid formation. In particular, we show that β -synuclein strongly suppresses both lipid-induced aggregation and secondary nucleation of α -synuclein by competing for binding sites at the surfaces of lipid vesicles and fibrils, respectively. These results suggest that β -synuclein can act as a natural inhibitor of α -synuclein aggregation by reducing both the initiation of its self-assembly and the proliferation of its aggregates.