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

James W P Brown; Alexander K Buell; Thomas C T Michaels; Georg Meisl; Jacqueline Carozza; Patrick Flagmeier; Michele Vendruscolo; Tuomas P J Knowles; Christopher M Dobson; Céline Galvagnion

doi:10.1038/srep36010

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

James W P Brown, Alexander K Buell, Thomas C T Michaels, Georg Meisl, Jacqueline Carozza, Patrick Flagmeier, Michele Vendruscolo, Tuomas P J Knowles, Christopher M Dobson, Céline Galvagnion

35 Citations (Scopus)

Abstract

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.

Original language	English
Journal	Scientific Reports
Volume	6
Pages (from-to)	36010
ISSN	2045-2322
DOIs	https://doi.org/10.1038/srep36010
Publication status	Published - 3 Nov 2016
Externally published	Yes

Keywords

Amino Acid Sequence
Binding, Competitive
Hydrogen-Ion Concentration
Lipids/chemistry
Phosphatidylserines/chemistry
Protein Aggregates
Protein Aggregation, Pathological
Protein Binding
Sequence Alignment
Surface Properties
alpha-Synuclein/chemistry
beta-Synuclein/chemistry

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Cite this

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

abstract = "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.",

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author = "Brown, {James W P} and Buell, {Alexander K} and Michaels, {Thomas C T} and Georg Meisl and Jacqueline Carozza and Patrick Flagmeier and Michele Vendruscolo and Knowles, {Tuomas P J} and Dobson, {Christopher M} and C{\'e}line Galvagnion",

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doi = "10.1038/srep36010",

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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 -

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

Abstract

Keywords

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