A β-Wrapin Targeting the N-Terminus of α-Synuclein Monomers Reduces Fibril-Induced Aggregation in Neurons
Reducing α-synuclein pathology constitutes a plausible strategy against Parkinson’s disease. As we recently demonstrated, the β-wrapin protein AS69 binds an N-terminal region in monomeric α-synuclein, interferes with fibril nucleation, and reduces α-synuclein aggregation in vitro and in a fruit fly...
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doaj-4afc3502a31946d28cb7ee107aa295032021-07-13T06:44:41ZengFrontiers Media S.A.Frontiers in Neuroscience1662-453X2021-07-011510.3389/fnins.2021.696440696440A β-Wrapin Targeting the N-Terminus of α-Synuclein Monomers Reduces Fibril-Induced Aggregation in NeuronsÉva M. Szegő0Fabian Boß1Daniel Komnig2Charlott Gärtner3Lennart Höfs4Hamed Shaykhalishahi5Hamed Shaykhalishahi6Michael M. Wördehoff7Theodora Saridaki8Jörg B. Schulz9Jörg B. Schulz10Wolfgang Hoyer11Wolfgang Hoyer12Björn H. Falkenburger13Björn H. Falkenburger14Björn H. Falkenburger15Björn H. Falkenburger16Department of Neurology, Technische Universität Dresden, Dresden, GermanyDepartment of Neurology, RWTH Aachen University, Aachen, GermanyDepartment of Neurology, RWTH Aachen University, Aachen, GermanyDepartment of Neurology, Technische Universität Dresden, Dresden, GermanyDepartment of Neurology, Technische Universität Dresden, Dresden, GermanyInstitut für Physikalische Biologie, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, GermanyInstitute of Biological Information Processing (IBI-7), Forschungszentrum Jülich GmbH, Jülich, GermanyInstitut für Physikalische Biologie, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, GermanyDepartment of Neurology, RWTH Aachen University, Aachen, GermanyDepartment of Neurology, RWTH Aachen University, Aachen, GermanyJARA-Institute Molecular Neuroscience and Neuroimaging, Forschungszentrum Jülich GmbH and RWTH Aachen University, Aachen, GermanyInstitut für Physikalische Biologie, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, GermanyInstitute of Biological Information Processing (IBI-7), Forschungszentrum Jülich GmbH, Jülich, GermanyDepartment of Neurology, Technische Universität Dresden, Dresden, GermanyDepartment of Neurology, RWTH Aachen University, Aachen, GermanyJARA-Institute Molecular Neuroscience and Neuroimaging, Forschungszentrum Jülich GmbH and RWTH Aachen University, Aachen, GermanyDeutsches Zentrum für Neurodegenerative Erkrankungen, Dresden, GermanyReducing α-synuclein pathology constitutes a plausible strategy against Parkinson’s disease. As we recently demonstrated, the β-wrapin protein AS69 binds an N-terminal region in monomeric α-synuclein, interferes with fibril nucleation, and reduces α-synuclein aggregation in vitro and in a fruit fly model of α-synuclein toxicity. The aim of this study was to investigate whether AS69 also reduces α-synuclein pathology in mammalian neurons. To induce α-synuclein pathology, primary mouse neurons were exposed to pre-formed fibrils (PFF) of human α-synuclein. PFF were also injected into the striatum of A30P-α-synuclein transgenic mice. The extent of α-synuclein pathology was determined by phospho-α-synuclein staining and by Triton X-100 solubility. The degeneration of neuronal somata, dendrites, and axon terminals was determined by immunohistochemistry. AS69 and PFF were taken up by primary neurons. AS69 did not alter PFF uptake, but AS69 did reduce PFF-induced α-synuclein pathology. PFF injection into mouse striatum led to α-synuclein pathology and dystrophic neurites. Co-injection of AS69 abrogated PFF-induced pathology. AS69 also reduced the PFF-induced degeneration of dopaminergic axon terminals in the striatum and the degeneration of dopaminergic dendrites in the substantia nigra pars reticulata. AS69 reduced the activation of astroglia but not microglia in response to PFF injection. Collectively, AS69 reduced PFF-induced α-synuclein pathology and the associated neurodegeneration in primary neurons and in mouse brain. Our data therefore suggest that small proteins binding the N-terminus of α-synuclein monomers are promising strategies to modify disease progression in Parkinson’s disease.https://www.frontiersin.org/articles/10.3389/fnins.2021.696440/fullα-synucleinpre-formed fibrilsprotein aggregationmolecular chaperonesnanobodies |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Éva M. Szegő Fabian Boß Daniel Komnig Charlott Gärtner Lennart Höfs Hamed Shaykhalishahi Hamed Shaykhalishahi Michael M. Wördehoff Theodora Saridaki Jörg B. Schulz Jörg B. Schulz Wolfgang Hoyer Wolfgang Hoyer Björn H. Falkenburger Björn H. Falkenburger Björn H. Falkenburger Björn H. Falkenburger |
spellingShingle |
Éva M. Szegő Fabian Boß Daniel Komnig Charlott Gärtner Lennart Höfs Hamed Shaykhalishahi Hamed Shaykhalishahi Michael M. Wördehoff Theodora Saridaki Jörg B. Schulz Jörg B. Schulz Wolfgang Hoyer Wolfgang Hoyer Björn H. Falkenburger Björn H. Falkenburger Björn H. Falkenburger Björn H. Falkenburger A β-Wrapin Targeting the N-Terminus of α-Synuclein Monomers Reduces Fibril-Induced Aggregation in Neurons Frontiers in Neuroscience α-synuclein pre-formed fibrils protein aggregation molecular chaperones nanobodies |
author_facet |
Éva M. Szegő Fabian Boß Daniel Komnig Charlott Gärtner Lennart Höfs Hamed Shaykhalishahi Hamed Shaykhalishahi Michael M. Wördehoff Theodora Saridaki Jörg B. Schulz Jörg B. Schulz Wolfgang Hoyer Wolfgang Hoyer Björn H. Falkenburger Björn H. Falkenburger Björn H. Falkenburger Björn H. Falkenburger |
author_sort |
Éva M. Szegő |
title |
A β-Wrapin Targeting the N-Terminus of α-Synuclein Monomers Reduces Fibril-Induced Aggregation in Neurons |
title_short |
A β-Wrapin Targeting the N-Terminus of α-Synuclein Monomers Reduces Fibril-Induced Aggregation in Neurons |
title_full |
A β-Wrapin Targeting the N-Terminus of α-Synuclein Monomers Reduces Fibril-Induced Aggregation in Neurons |
title_fullStr |
A β-Wrapin Targeting the N-Terminus of α-Synuclein Monomers Reduces Fibril-Induced Aggregation in Neurons |
title_full_unstemmed |
A β-Wrapin Targeting the N-Terminus of α-Synuclein Monomers Reduces Fibril-Induced Aggregation in Neurons |
title_sort |
β-wrapin targeting the n-terminus of α-synuclein monomers reduces fibril-induced aggregation in neurons |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Neuroscience |
issn |
1662-453X |
publishDate |
2021-07-01 |
description |
Reducing α-synuclein pathology constitutes a plausible strategy against Parkinson’s disease. As we recently demonstrated, the β-wrapin protein AS69 binds an N-terminal region in monomeric α-synuclein, interferes with fibril nucleation, and reduces α-synuclein aggregation in vitro and in a fruit fly model of α-synuclein toxicity. The aim of this study was to investigate whether AS69 also reduces α-synuclein pathology in mammalian neurons. To induce α-synuclein pathology, primary mouse neurons were exposed to pre-formed fibrils (PFF) of human α-synuclein. PFF were also injected into the striatum of A30P-α-synuclein transgenic mice. The extent of α-synuclein pathology was determined by phospho-α-synuclein staining and by Triton X-100 solubility. The degeneration of neuronal somata, dendrites, and axon terminals was determined by immunohistochemistry. AS69 and PFF were taken up by primary neurons. AS69 did not alter PFF uptake, but AS69 did reduce PFF-induced α-synuclein pathology. PFF injection into mouse striatum led to α-synuclein pathology and dystrophic neurites. Co-injection of AS69 abrogated PFF-induced pathology. AS69 also reduced the PFF-induced degeneration of dopaminergic axon terminals in the striatum and the degeneration of dopaminergic dendrites in the substantia nigra pars reticulata. AS69 reduced the activation of astroglia but not microglia in response to PFF injection. Collectively, AS69 reduced PFF-induced α-synuclein pathology and the associated neurodegeneration in primary neurons and in mouse brain. Our data therefore suggest that small proteins binding the N-terminus of α-synuclein monomers are promising strategies to modify disease progression in Parkinson’s disease. |
topic |
α-synuclein pre-formed fibrils protein aggregation molecular chaperones nanobodies |
url |
https://www.frontiersin.org/articles/10.3389/fnins.2021.696440/full |
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