[beta]-Synuclein suppresses both the initiation and amplification steps of [alpha]-synuclein aggregation via competitive binding to surfaces

• Published in: Scientific reports Vol. 6; 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 01.11.2016
• Subjects: Amyloid; Binding sites; Fibrillogenesis; Molecular structure; Movement disorders; Neurodegenerative diseases; Nucleation; Parkinson's disease; Self-assembly; Synuclein
• ISSN: 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.