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

TY - JOUR

T1 - β-Synuclein suppresses both the initiation and amplification steps of α-synuclein aggregation via competitive binding to surfaces

AU - Brown, James W P

AU - Buell, Alexander K

AU - Michaels, Thomas C T

AU - Meisl, Georg

AU - Carozza, Jacqueline

AU - Flagmeier, Patrick

AU - Vendruscolo, Michele

AU - Knowles, Tuomas P J

AU - Dobson, Christopher M

AU - Galvagnion, Céline

PY - 2016/11/3

Y1 - 2016/11/3

N2 - 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.

AB - 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.

KW - Amino Acid Sequence

KW - Binding, Competitive

KW - Hydrogen-Ion Concentration

KW - Lipids/chemistry

KW - Phosphatidylserines/chemistry

KW - Protein Aggregates

KW - Protein Aggregation, Pathological

KW - Protein Binding

KW - Sequence Alignment

KW - Surface Properties

KW - alpha-Synuclein/chemistry

KW - beta-Synuclein/chemistry

U2 - 10.1038/srep36010

DO - 10.1038/srep36010

M3 - Journal article

C2 - 27808107

SN - 2045-2322

VL - 6

SP - 36010

JO - Scientific Reports

JF - Scientific Reports

ER -