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Co-aggregation of pro-inflammatory S100A9 with α-synuclein in Parkinson’s disease: ex vivo and in vitro studies

BACKGROUND: Chronic neuroinflammation is a hallmark of Parkinson’s disease (PD) pathophysiology, associated with increased levels of pro-inflammatory factors in PD brain tissues. The pro-inflammatory mediator and highly amyloidogenic protein S100A9 is involved in the amyloid-neuroinflammatory cascad...

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Autores principales: Horvath, Istvan, Iashchishyn, Igor A., Moskalenko, Roman A., Wang, Chao, Wärmländer, Sebastian K. T. S., Wallin, Cecilia, Gräslund, Astrid, Kovacs, Gabor G., Morozova-Roche, Ludmilla A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5987543/
https://www.ncbi.nlm.nih.gov/pubmed/29866153
http://dx.doi.org/10.1186/s12974-018-1210-9
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author Horvath, Istvan
Iashchishyn, Igor A.
Moskalenko, Roman A.
Wang, Chao
Wärmländer, Sebastian K. T. S.
Wallin, Cecilia
Gräslund, Astrid
Kovacs, Gabor G.
Morozova-Roche, Ludmilla A.
author_facet Horvath, Istvan
Iashchishyn, Igor A.
Moskalenko, Roman A.
Wang, Chao
Wärmländer, Sebastian K. T. S.
Wallin, Cecilia
Gräslund, Astrid
Kovacs, Gabor G.
Morozova-Roche, Ludmilla A.
author_sort Horvath, Istvan
collection PubMed
description BACKGROUND: Chronic neuroinflammation is a hallmark of Parkinson’s disease (PD) pathophysiology, associated with increased levels of pro-inflammatory factors in PD brain tissues. The pro-inflammatory mediator and highly amyloidogenic protein S100A9 is involved in the amyloid-neuroinflammatory cascade in Alzheimer’s disease. This is the first report on the co-aggregation of α-synuclein (α-syn) and S100A9 both in vitro and ex vivo in PD brain. METHODS: Single and sequential immunohistochemistry, immunofluorescence, scanning electron and atomic force (AFM) microscopies were used to analyze the ex vivo PD brain tissues for S100A9 and α-syn location and aggregation. In vitro studies revealing S100A9 and α-syn interaction and co-aggregation were conducted by NMR, circular dichroism, Thioflavin-T fluorescence, AFM, and surface plasmon resonance methods. RESULTS: Co-localized and co-aggregated S100A9 and α-syn were found in 20% Lewy bodies and 77% neuronal cells in the substantia nigra; both proteins were also observed in Lewy bodies in PD frontal lobe (Braak stages 4–6). Lewy bodies were characterized by ca. 10–23 μm outer diameter, with S100A9 and α-syn being co-localized in the same lamellar structures. S100A9 was also detected in neurons and blood vessels of the aged patients without PD, but in much lesser extent. In vitro S100A9 and α-syn were shown to interact with each other via the α-syn C-terminus with an apparent dissociation constant of ca. 5 μM. Their co-aggregation occurred significantly faster and led to formation of larger amyloid aggregates than the self-assembly of individual proteins. S100A9 amyloid oligomers were more toxic than those of α-syn, while co-aggregation of both proteins mitigated the cytotoxicity of S100A9 oligomers. CONCLUSIONS: We suggest that sustained neuroinflammation promoting the spread of amyloidogenic S100A9 in the brain tissues may trigger the amyloid cascade involving α-syn and S100A9 and leading to PD, similar to the effect of S100A9 and Aβ co-aggregation in Alzheimer’s disease. The finding of S100A9 involvement in PD may open a new avenue for therapeutic interventions targeting S100A9 and preventing its amyloid self-assembly in affected brain tissues. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12974-018-1210-9) contains supplementary material, which is available to authorized users.
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spelling pubmed-59875432018-07-10 Co-aggregation of pro-inflammatory S100A9 with α-synuclein in Parkinson’s disease: ex vivo and in vitro studies Horvath, Istvan Iashchishyn, Igor A. Moskalenko, Roman A. Wang, Chao Wärmländer, Sebastian K. T. S. Wallin, Cecilia Gräslund, Astrid Kovacs, Gabor G. Morozova-Roche, Ludmilla A. J Neuroinflammation Research BACKGROUND: Chronic neuroinflammation is a hallmark of Parkinson’s disease (PD) pathophysiology, associated with increased levels of pro-inflammatory factors in PD brain tissues. The pro-inflammatory mediator and highly amyloidogenic protein S100A9 is involved in the amyloid-neuroinflammatory cascade in Alzheimer’s disease. This is the first report on the co-aggregation of α-synuclein (α-syn) and S100A9 both in vitro and ex vivo in PD brain. METHODS: Single and sequential immunohistochemistry, immunofluorescence, scanning electron and atomic force (AFM) microscopies were used to analyze the ex vivo PD brain tissues for S100A9 and α-syn location and aggregation. In vitro studies revealing S100A9 and α-syn interaction and co-aggregation were conducted by NMR, circular dichroism, Thioflavin-T fluorescence, AFM, and surface plasmon resonance methods. RESULTS: Co-localized and co-aggregated S100A9 and α-syn were found in 20% Lewy bodies and 77% neuronal cells in the substantia nigra; both proteins were also observed in Lewy bodies in PD frontal lobe (Braak stages 4–6). Lewy bodies were characterized by ca. 10–23 μm outer diameter, with S100A9 and α-syn being co-localized in the same lamellar structures. S100A9 was also detected in neurons and blood vessels of the aged patients without PD, but in much lesser extent. In vitro S100A9 and α-syn were shown to interact with each other via the α-syn C-terminus with an apparent dissociation constant of ca. 5 μM. Their co-aggregation occurred significantly faster and led to formation of larger amyloid aggregates than the self-assembly of individual proteins. S100A9 amyloid oligomers were more toxic than those of α-syn, while co-aggregation of both proteins mitigated the cytotoxicity of S100A9 oligomers. CONCLUSIONS: We suggest that sustained neuroinflammation promoting the spread of amyloidogenic S100A9 in the brain tissues may trigger the amyloid cascade involving α-syn and S100A9 and leading to PD, similar to the effect of S100A9 and Aβ co-aggregation in Alzheimer’s disease. The finding of S100A9 involvement in PD may open a new avenue for therapeutic interventions targeting S100A9 and preventing its amyloid self-assembly in affected brain tissues. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12974-018-1210-9) contains supplementary material, which is available to authorized users. BioMed Central 2018-06-04 /pmc/articles/PMC5987543/ /pubmed/29866153 http://dx.doi.org/10.1186/s12974-018-1210-9 Text en © The Author(s). 2018 Open Access This 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
Horvath, Istvan
Iashchishyn, Igor A.
Moskalenko, Roman A.
Wang, Chao
Wärmländer, Sebastian K. T. S.
Wallin, Cecilia
Gräslund, Astrid
Kovacs, Gabor G.
Morozova-Roche, Ludmilla A.
Co-aggregation of pro-inflammatory S100A9 with α-synuclein in Parkinson’s disease: ex vivo and in vitro studies
title Co-aggregation of pro-inflammatory S100A9 with α-synuclein in Parkinson’s disease: ex vivo and in vitro studies
title_full Co-aggregation of pro-inflammatory S100A9 with α-synuclein in Parkinson’s disease: ex vivo and in vitro studies
title_fullStr Co-aggregation of pro-inflammatory S100A9 with α-synuclein in Parkinson’s disease: ex vivo and in vitro studies
title_full_unstemmed Co-aggregation of pro-inflammatory S100A9 with α-synuclein in Parkinson’s disease: ex vivo and in vitro studies
title_short Co-aggregation of pro-inflammatory S100A9 with α-synuclein in Parkinson’s disease: ex vivo and in vitro studies
title_sort co-aggregation of pro-inflammatory s100a9 with α-synuclein in parkinson’s disease: ex vivo and in vitro studies
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5987543/
https://www.ncbi.nlm.nih.gov/pubmed/29866153
http://dx.doi.org/10.1186/s12974-018-1210-9
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