An engineered monomer binding-protein for α-synuclein efficiently inhibits the proliferation of amyloid fibrils
Removing or preventing the formation of [Formula: see text]-synuclein aggregates is a plausible strategy against Parkinson’s disease. To this end, we have engineered the [Formula: see text]-wrapin AS69 to bind monomeric [Formula: see text]-synuclein with high affinity. In cultured cells, AS69 reduce...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2019-08-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/46112 |
| _version_ | 1811181013101969408 |
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| author | Emil Dandanell Agerschou Patrick Flagmeier Theodora Saridaki Céline Galvagnion Daniel Komnig Laetitia Heid Vibha Prasad Hamed Shaykhalishahi Dieter Willbold Christopher M Dobson Aaron Voigt Bjoern Falkenburger Wolfgang Hoyer Alexander K Buell |
| author_facet | Emil Dandanell Agerschou Patrick Flagmeier Theodora Saridaki Céline Galvagnion Daniel Komnig Laetitia Heid Vibha Prasad Hamed Shaykhalishahi Dieter Willbold Christopher M Dobson Aaron Voigt Bjoern Falkenburger Wolfgang Hoyer Alexander K Buell |
| author_sort | Emil Dandanell Agerschou |
| collection | DOAJ |
| description | Removing or preventing the formation of [Formula: see text]-synuclein aggregates is a plausible strategy against Parkinson’s disease. To this end, we have engineered the [Formula: see text]-wrapin AS69 to bind monomeric [Formula: see text]-synuclein with high affinity. In cultured cells, AS69 reduced the self-interaction of [Formula: see text]-synuclein and formation of visible [Formula: see text]-synuclein aggregates. In flies, AS69 reduced [Formula: see text]-synuclein aggregates and the locomotor deficit resulting from [Formula: see text]-synuclein expression in neuronal cells. In biophysical experiments in vitro, AS69 highly sub-stoichiometrically inhibited both primary and autocatalytic secondary nucleation processes, even in the presence of a large excess of monomer. We present evidence that the AS69-[Formula: see text]-synuclein complex, rather than the free AS69, is the inhibitory species responsible for sub-stoichiometric inhibition of secondary nucleation. These results represent a new paradigm that high affinity monomer binders can lead to strongly sub-stoichiometric inhibition of nucleation processes. |
| first_indexed | 2024-04-11T09:11:12Z |
| format | Article |
| id | doaj.art-1487d7db37e74f7e9d5d15b7c82df34c |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T09:11:12Z |
| publishDate | 2019-08-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-1487d7db37e74f7e9d5d15b7c82df34c2022-12-22T04:32:29ZengeLife Sciences Publications LtdeLife2050-084X2019-08-01810.7554/eLife.46112An engineered monomer binding-protein for α-synuclein efficiently inhibits the proliferation of amyloid fibrilsEmil Dandanell Agerschou0Patrick Flagmeier1https://orcid.org/0000-0002-1204-5340Theodora Saridaki2Céline Galvagnion3Daniel Komnig4https://orcid.org/0000-0002-6312-5236Laetitia Heid5Vibha Prasad6Hamed Shaykhalishahi7Dieter Willbold8https://orcid.org/0000-0002-0065-7366Christopher M Dobson9Aaron Voigt10https://orcid.org/0000-0002-0428-7462Bjoern Falkenburger11https://orcid.org/0000-0002-2387-526XWolfgang Hoyer12https://orcid.org/0000-0003-4301-5416Alexander K Buell13https://orcid.org/0000-0003-1161-3622Institut für Physikalische Biologie, Heinrich Heine University Düsseldorf, Düsseldorf, GermanyDepartment of Chemistry, University of Cambridge, Cambridge, United Kingdom; Centre for Misfolding Diseases, University of Cambridge, Cambridge, United KingdomDepartment of Neurology, RWTH Aachen University, Aachen, GermanyRG Mechanisms of Neuroprotection, German Centre for Neurodegenerative Diseases (DZNE), Bonn, Germany; Department of Pharmacology and Drug Design, University of Copenhagen, Copenhagen, DenmarkDepartment of Neurology, RWTH Aachen University, Aachen, GermanyInstitut für Physikalische Biologie, Heinrich Heine University Düsseldorf, Düsseldorf, GermanyDepartment of Neurology, RWTH Aachen University, Aachen, GermanyInstitut für Physikalische Biologie, Heinrich Heine University Düsseldorf, Düsseldorf, GermanyInstitut für Physikalische Biologie, Heinrich Heine University Düsseldorf, Düsseldorf, Germany; Institute of Complex Systems (ICS-6), Structural Biochemistry, Forschungszentrum Jülich, Jülich, GermanyDepartment of Chemistry, University of Cambridge, Cambridge, United Kingdom; Centre for Misfolding Diseases, University of Cambridge, Cambridge, United KingdomDepartment of Neurology, RWTH Aachen University, Aachen, GermanyDepartment of Neurology, RWTH Aachen University, Aachen, Germany; Department of Neurology, Dresden University Medical Center, Dresden, Germany; JARA BRAIN Institute II, Julich and Aachen, GermanyInstitut für Physikalische Biologie, Heinrich Heine University Düsseldorf, Düsseldorf, Germany; Institute of Complex Systems (ICS-6), Structural Biochemistry, Forschungszentrum Jülich, Jülich, GermanyInstitut für Physikalische Biologie, Heinrich Heine University Düsseldorf, Düsseldorf, Germany; Department of Biotechnology and Biomedicine, Technical University of Denmark, Kgs. Lyngby, DenmarkRemoving or preventing the formation of [Formula: see text]-synuclein aggregates is a plausible strategy against Parkinson’s disease. To this end, we have engineered the [Formula: see text]-wrapin AS69 to bind monomeric [Formula: see text]-synuclein with high affinity. In cultured cells, AS69 reduced the self-interaction of [Formula: see text]-synuclein and formation of visible [Formula: see text]-synuclein aggregates. In flies, AS69 reduced [Formula: see text]-synuclein aggregates and the locomotor deficit resulting from [Formula: see text]-synuclein expression in neuronal cells. In biophysical experiments in vitro, AS69 highly sub-stoichiometrically inhibited both primary and autocatalytic secondary nucleation processes, even in the presence of a large excess of monomer. We present evidence that the AS69-[Formula: see text]-synuclein complex, rather than the free AS69, is the inhibitory species responsible for sub-stoichiometric inhibition of secondary nucleation. These results represent a new paradigm that high affinity monomer binders can lead to strongly sub-stoichiometric inhibition of nucleation processes.https://elifesciences.org/articles/46112amyloidinhibtionnucleationβ-wrapinAS69Parkinson's disease |
| spellingShingle | Emil Dandanell Agerschou Patrick Flagmeier Theodora Saridaki Céline Galvagnion Daniel Komnig Laetitia Heid Vibha Prasad Hamed Shaykhalishahi Dieter Willbold Christopher M Dobson Aaron Voigt Bjoern Falkenburger Wolfgang Hoyer Alexander K Buell An engineered monomer binding-protein for α-synuclein efficiently inhibits the proliferation of amyloid fibrils eLife amyloid inhibtion nucleation β-wrapin AS69 Parkinson's disease |
| title | An engineered monomer binding-protein for α-synuclein efficiently inhibits the proliferation of amyloid fibrils |
| title_full | An engineered monomer binding-protein for α-synuclein efficiently inhibits the proliferation of amyloid fibrils |
| title_fullStr | An engineered monomer binding-protein for α-synuclein efficiently inhibits the proliferation of amyloid fibrils |
| title_full_unstemmed | An engineered monomer binding-protein for α-synuclein efficiently inhibits the proliferation of amyloid fibrils |
| title_short | An engineered monomer binding-protein for α-synuclein efficiently inhibits the proliferation of amyloid fibrils |
| title_sort | engineered monomer binding protein for α synuclein efficiently inhibits the proliferation of amyloid fibrils |
| topic | amyloid inhibtion nucleation β-wrapin AS69 Parkinson's disease |
| url | https://elifesciences.org/articles/46112 |
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