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Fasudil attenuates aggregation of α-synuclein in models of Parkinson’s disease
Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, yet disease-modifying treatments do not currently exist. Rho-associated protein kinase (ROCK) was recently described as a novel neuroprotective target in PD. Since alpha-synuclein (α-Syn) aggregation is a major hallmark...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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BioMed Central
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4840958/ https://www.ncbi.nlm.nih.gov/pubmed/27101974 http://dx.doi.org/10.1186/s40478-016-0310-y |
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author | Tatenhorst, Lars Eckermann, Katrin Dambeck, Vivian Fonseca-Ornelas, Luis Walle, Hagen Lopes da Fonseca, Tomás Koch, Jan C. Becker, Stefan Tönges, Lars Bähr, Mathias Outeiro, Tiago F. Zweckstetter, Markus Lingor, Paul |
author_facet | Tatenhorst, Lars Eckermann, Katrin Dambeck, Vivian Fonseca-Ornelas, Luis Walle, Hagen Lopes da Fonseca, Tomás Koch, Jan C. Becker, Stefan Tönges, Lars Bähr, Mathias Outeiro, Tiago F. Zweckstetter, Markus Lingor, Paul |
author_sort | Tatenhorst, Lars |
collection | PubMed |
description | Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, yet disease-modifying treatments do not currently exist. Rho-associated protein kinase (ROCK) was recently described as a novel neuroprotective target in PD. Since alpha-synuclein (α-Syn) aggregation is a major hallmark in the pathogenesis of PD, we aimed to evaluate the anti-aggregative potential of pharmacological ROCK inhibition using the isoquinoline derivative Fasudil, a small molecule inhibitor already approved for clinical use in humans. Fasudil treatment significantly reduced α-Syn aggregation in vitro in a H4 cell culture model as well as in a cell-free assay. Nuclear magnetic resonance spectroscopy analysis revealed a direct binding of Fasudil to tyrosine residues Y133 and Y136 in the C-terminal region of α-Syn. Importantly, this binding was shown to be biologically relevant using site-directed mutagenesis of these residues in the cell culture model. Furthermore, we evaluated the impact of long-term Fasudil treatment on α-Syn pathology in vivo in a transgenic mouse model overexpressing human α-Syn bearing the A53T mutation (α-Syn(A53T) mice). Fasudil treatment improved motor and cognitive functions in α-Syn(A53T) mice as determined by Catwalk(TM) gait analysis and novel object recognition (NOR), without apparent side effects. Finally, immunohistochemical analysis revealed a significant reduction of α-Syn pathology in the midbrain of α-Syn(A53T) mice after Fasudil treatment. Our results demonstrate that Fasudil, next to its effects mediated by ROCK-inhibition, directly interacts with α-Syn and attenuates α-Syn pathology. This underscores the translational potential of Fasudil as a disease-modifying drug for the treatment of PD and other synucleinopathies. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40478-016-0310-y) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-4840958 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-48409582016-04-23 Fasudil attenuates aggregation of α-synuclein in models of Parkinson’s disease Tatenhorst, Lars Eckermann, Katrin Dambeck, Vivian Fonseca-Ornelas, Luis Walle, Hagen Lopes da Fonseca, Tomás Koch, Jan C. Becker, Stefan Tönges, Lars Bähr, Mathias Outeiro, Tiago F. Zweckstetter, Markus Lingor, Paul Acta Neuropathol Commun Research Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, yet disease-modifying treatments do not currently exist. Rho-associated protein kinase (ROCK) was recently described as a novel neuroprotective target in PD. Since alpha-synuclein (α-Syn) aggregation is a major hallmark in the pathogenesis of PD, we aimed to evaluate the anti-aggregative potential of pharmacological ROCK inhibition using the isoquinoline derivative Fasudil, a small molecule inhibitor already approved for clinical use in humans. Fasudil treatment significantly reduced α-Syn aggregation in vitro in a H4 cell culture model as well as in a cell-free assay. Nuclear magnetic resonance spectroscopy analysis revealed a direct binding of Fasudil to tyrosine residues Y133 and Y136 in the C-terminal region of α-Syn. Importantly, this binding was shown to be biologically relevant using site-directed mutagenesis of these residues in the cell culture model. Furthermore, we evaluated the impact of long-term Fasudil treatment on α-Syn pathology in vivo in a transgenic mouse model overexpressing human α-Syn bearing the A53T mutation (α-Syn(A53T) mice). Fasudil treatment improved motor and cognitive functions in α-Syn(A53T) mice as determined by Catwalk(TM) gait analysis and novel object recognition (NOR), without apparent side effects. Finally, immunohistochemical analysis revealed a significant reduction of α-Syn pathology in the midbrain of α-Syn(A53T) mice after Fasudil treatment. Our results demonstrate that Fasudil, next to its effects mediated by ROCK-inhibition, directly interacts with α-Syn and attenuates α-Syn pathology. This underscores the translational potential of Fasudil as a disease-modifying drug for the treatment of PD and other synucleinopathies. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40478-016-0310-y) contains supplementary material, which is available to authorized users. BioMed Central 2016-04-22 /pmc/articles/PMC4840958/ /pubmed/27101974 http://dx.doi.org/10.1186/s40478-016-0310-y Text en © Tatenhorst et al. 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Tatenhorst, Lars Eckermann, Katrin Dambeck, Vivian Fonseca-Ornelas, Luis Walle, Hagen Lopes da Fonseca, Tomás Koch, Jan C. Becker, Stefan Tönges, Lars Bähr, Mathias Outeiro, Tiago F. Zweckstetter, Markus Lingor, Paul Fasudil attenuates aggregation of α-synuclein in models of Parkinson’s disease |
title | Fasudil attenuates aggregation of α-synuclein in models of Parkinson’s disease |
title_full | Fasudil attenuates aggregation of α-synuclein in models of Parkinson’s disease |
title_fullStr | Fasudil attenuates aggregation of α-synuclein in models of Parkinson’s disease |
title_full_unstemmed | Fasudil attenuates aggregation of α-synuclein in models of Parkinson’s disease |
title_short | Fasudil attenuates aggregation of α-synuclein in models of Parkinson’s disease |
title_sort | fasudil attenuates aggregation of α-synuclein in models of parkinson’s disease |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4840958/ https://www.ncbi.nlm.nih.gov/pubmed/27101974 http://dx.doi.org/10.1186/s40478-016-0310-y |
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