Unveiling a Selective Mechanism for the Inhibition of α-Synuclein Aggregation by β-Synuclein
α-Synuclein (αS) is an intrinsically disordered protein that is associated with Parkinson’s disease (PD) through its ability to self-assemble into oligomers and fibrils. Inhibition of this oligomerization cascade is an interesting approach to developing therapeutical strategies and β-synuclein (βS)...
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doaj-58dc77e8bf344b809985b0370e0228d02020-11-24T22:21:23ZengMDPI AGInternational Journal of Molecular Sciences1422-00672018-01-0119233410.3390/ijms19020334ijms19020334Unveiling a Selective Mechanism for the Inhibition of α-Synuclein Aggregation by β-SynucleinAndre Leitao0Akshay Bhumkar1Dominic J. B. Hunter2Yann Gambin3Emma Sierecki4European Molecular Biology Laboratory (EMBL), Australia Node in Single Molecule Science, Sydney NSW 2031, AustraliaEuropean Molecular Biology Laboratory (EMBL), Australia Node in Single Molecule Science, Sydney NSW 2031, AustraliaEuropean Molecular Biology Laboratory (EMBL), Australia Node in Single Molecule Science, Sydney NSW 2031, AustraliaEuropean Molecular Biology Laboratory (EMBL), Australia Node in Single Molecule Science, Sydney NSW 2031, AustraliaEuropean Molecular Biology Laboratory (EMBL), Australia Node in Single Molecule Science, Sydney NSW 2031, Australiaα-Synuclein (αS) is an intrinsically disordered protein that is associated with Parkinson’s disease (PD) through its ability to self-assemble into oligomers and fibrils. Inhibition of this oligomerization cascade is an interesting approach to developing therapeutical strategies and β-synuclein (βS) has been described as a natural negative regulator of this process. However, the biological background and molecular mechanisms by which this inhibition occurs is unclear. Herein, we focused on assessing the effect of βS on the aggregation of five αS pathological mutants linked to early-onset PD (A30P, E46K, H50Q, G51D and A53T). By coupling single molecule fluorescence spectroscopy to a cell-free protein expression system, we validated the ability of βS to act as a chaperone of αS, effectively inhibiting its aggregation. Interestingly, we found that βS does so in a selective manner, i.e., is a more effective inhibitor for certain αS pathological mutants—A30P and G51D—as compared to E46K, H50Q and A53T. Moreover, two-color coincidence experiments proved that this discrepancy is due to a preferential incorporation of βS into smaller oligomers of αS. This was validated by showing that the chaperoning effect was lost when proteins were mixed after being expressed individually. This study highlights the potential of fluorescence spectroscopy to deconstruct αS aggregation cascade and its interplay with βS.http://www.mdpi.com/1422-0067/19/2/334α-synucleinβ-synucleinParkinson’s diseaseprotein oligomerizationsingle molecule spectroscopynumber and brightness analysistwo-color coincidence |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Andre Leitao Akshay Bhumkar Dominic J. B. Hunter Yann Gambin Emma Sierecki |
spellingShingle |
Andre Leitao Akshay Bhumkar Dominic J. B. Hunter Yann Gambin Emma Sierecki Unveiling a Selective Mechanism for the Inhibition of α-Synuclein Aggregation by β-Synuclein International Journal of Molecular Sciences α-synuclein β-synuclein Parkinson’s disease protein oligomerization single molecule spectroscopy number and brightness analysis two-color coincidence |
author_facet |
Andre Leitao Akshay Bhumkar Dominic J. B. Hunter Yann Gambin Emma Sierecki |
author_sort |
Andre Leitao |
title |
Unveiling a Selective Mechanism for the Inhibition of α-Synuclein Aggregation by β-Synuclein |
title_short |
Unveiling a Selective Mechanism for the Inhibition of α-Synuclein Aggregation by β-Synuclein |
title_full |
Unveiling a Selective Mechanism for the Inhibition of α-Synuclein Aggregation by β-Synuclein |
title_fullStr |
Unveiling a Selective Mechanism for the Inhibition of α-Synuclein Aggregation by β-Synuclein |
title_full_unstemmed |
Unveiling a Selective Mechanism for the Inhibition of α-Synuclein Aggregation by β-Synuclein |
title_sort |
unveiling a selective mechanism for the inhibition of α-synuclein aggregation by β-synuclein |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1422-0067 |
publishDate |
2018-01-01 |
description |
α-Synuclein (αS) is an intrinsically disordered protein that is associated with Parkinson’s disease (PD) through its ability to self-assemble into oligomers and fibrils. Inhibition of this oligomerization cascade is an interesting approach to developing therapeutical strategies and β-synuclein (βS) has been described as a natural negative regulator of this process. However, the biological background and molecular mechanisms by which this inhibition occurs is unclear. Herein, we focused on assessing the effect of βS on the aggregation of five αS pathological mutants linked to early-onset PD (A30P, E46K, H50Q, G51D and A53T). By coupling single molecule fluorescence spectroscopy to a cell-free protein expression system, we validated the ability of βS to act as a chaperone of αS, effectively inhibiting its aggregation. Interestingly, we found that βS does so in a selective manner, i.e., is a more effective inhibitor for certain αS pathological mutants—A30P and G51D—as compared to E46K, H50Q and A53T. Moreover, two-color coincidence experiments proved that this discrepancy is due to a preferential incorporation of βS into smaller oligomers of αS. This was validated by showing that the chaperoning effect was lost when proteins were mixed after being expressed individually. This study highlights the potential of fluorescence spectroscopy to deconstruct αS aggregation cascade and its interplay with βS. |
topic |
α-synuclein β-synuclein Parkinson’s disease protein oligomerization single molecule spectroscopy number and brightness analysis two-color coincidence |
url |
http://www.mdpi.com/1422-0067/19/2/334 |
work_keys_str_mv |
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