β-Synuclein suppresses both the initiation and amplification steps of α-synuclein aggregation via competitive binding to surfaces.
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.
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
James W P
JW
Brown
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
Alexander K
AK
Buell
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
Thomas C T
TC
Michaels
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
Georg
G
Meisl
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
Jacqueline
J
Carozza
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
Patrick
P
Flagmeier
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
Michele
M
Vendruscolo
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
Tuomas P J
TP
Knowles
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
Christopher M
CM
Dobson
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
Céline
C
Galvagnion
D000595:Amino Acid Sequence; D001667:Binding, Competitive; D006863:Hydrogen-Ion Concentration; D008055:Lipids / Q000737:chemistry; D010718:Phosphatidylserines / Q000737:chemistry; D066329:Protein Aggregates; D066263:Protein Aggregation, Pathological; D011485:Protein Binding; D016415:Sequence Alignment; D013499:Surface Properties; D051844:alpha-Synuclein / Q000737:chemistry* / Q000378:metabolism*; D051846:beta-Synuclein / Q000737:chemistry / Q000378:metabolism*
D008055:Lipids; D010718:Phosphatidylserines; D066329:Protein Aggregates; D051844:alpha-Synuclein; D051846:beta-Synuclein; C042859:dimyristoylphosphatidylserine