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Fractalkine Signaling Regulates the Inflammatory Response in an α-Synuclein Model of Parkinson Disease
BACKGROUND: Parkinson disease (PD) is a progressive neurodegenerative disorder characterized by loss of dopamine neurons in the substantia nigra pars compacta (SNpc) and widespread aggregates of the protein alpha-synuclein (α-syn). Increasing evidence points to inflammation as a chief mediator; howe...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4607155/ https://www.ncbi.nlm.nih.gov/pubmed/26469270 http://dx.doi.org/10.1371/journal.pone.0140566 |
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author | Thome, Aaron D. Standaert, David G. Harms, Ashley S. |
author_facet | Thome, Aaron D. Standaert, David G. Harms, Ashley S. |
author_sort | Thome, Aaron D. |
collection | PubMed |
description | BACKGROUND: Parkinson disease (PD) is a progressive neurodegenerative disorder characterized by loss of dopamine neurons in the substantia nigra pars compacta (SNpc) and widespread aggregates of the protein alpha-synuclein (α-syn). Increasing evidence points to inflammation as a chief mediator; however, the role of α-syn in triggering and sustaining inflammation remains unclear. In models of Alzheimer’s disease (AD), multiple sclerosis (MS) and neurotoxin models of PD, the chemokine CX3CL1 (fractalkine) and its receptor (CX3CR1) have important roles in modulating neuroinflammation. METHODS: To examine the role of fractalkine signaling in α-syn-induced-neuroinflammation and neurodegeneration, we used an in vivo mouse model in which human α-syn is overexpressed by an adeno associated viral vector serotype 2 (AAV2) and in vitro phagocytosis and protein internalization assays with primary microglia treated with aggregated α-syn. RESULTS: We observed that loss of CX3CR1 expression led to a reduced inflammatory response, with reduced IgG deposition and expression of MHCII 4 weeks post-transduction. Six months post transduction, AAV2 mediated overexpression of α-syn leads to loss of dopaminergic neurons, and this loss was not exacerbated in animals with deletion of CX3CR1. To determine the mechanism by which CX3CR1affects inflammatory responses in α-syn-induced inflammation, phagocytosis was assessed using a fluorescent microsphere assay as well as by microglial uptake of aggregated α-syn. CX3CR1-/- microglia showed reduced uptake of fluorescent beads and aggregated α-syn. CONCLUSION: Our results suggest that one mechanism by which CX3CR1-/- attenuates inflammation is at the level of phagocytosis of aggregated α-syn by microglia. These data implicate fractalkine signaling as a potential therapeutic target for regulating inflammatory response in α-syn models PD. |
format | Online Article Text |
id | pubmed-4607155 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-46071552015-10-29 Fractalkine Signaling Regulates the Inflammatory Response in an α-Synuclein Model of Parkinson Disease Thome, Aaron D. Standaert, David G. Harms, Ashley S. PLoS One Research Article BACKGROUND: Parkinson disease (PD) is a progressive neurodegenerative disorder characterized by loss of dopamine neurons in the substantia nigra pars compacta (SNpc) and widespread aggregates of the protein alpha-synuclein (α-syn). Increasing evidence points to inflammation as a chief mediator; however, the role of α-syn in triggering and sustaining inflammation remains unclear. In models of Alzheimer’s disease (AD), multiple sclerosis (MS) and neurotoxin models of PD, the chemokine CX3CL1 (fractalkine) and its receptor (CX3CR1) have important roles in modulating neuroinflammation. METHODS: To examine the role of fractalkine signaling in α-syn-induced-neuroinflammation and neurodegeneration, we used an in vivo mouse model in which human α-syn is overexpressed by an adeno associated viral vector serotype 2 (AAV2) and in vitro phagocytosis and protein internalization assays with primary microglia treated with aggregated α-syn. RESULTS: We observed that loss of CX3CR1 expression led to a reduced inflammatory response, with reduced IgG deposition and expression of MHCII 4 weeks post-transduction. Six months post transduction, AAV2 mediated overexpression of α-syn leads to loss of dopaminergic neurons, and this loss was not exacerbated in animals with deletion of CX3CR1. To determine the mechanism by which CX3CR1affects inflammatory responses in α-syn-induced inflammation, phagocytosis was assessed using a fluorescent microsphere assay as well as by microglial uptake of aggregated α-syn. CX3CR1-/- microglia showed reduced uptake of fluorescent beads and aggregated α-syn. CONCLUSION: Our results suggest that one mechanism by which CX3CR1-/- attenuates inflammation is at the level of phagocytosis of aggregated α-syn by microglia. These data implicate fractalkine signaling as a potential therapeutic target for regulating inflammatory response in α-syn models PD. Public Library of Science 2015-10-15 /pmc/articles/PMC4607155/ /pubmed/26469270 http://dx.doi.org/10.1371/journal.pone.0140566 Text en © 2015 Thome et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Thome, Aaron D. Standaert, David G. Harms, Ashley S. Fractalkine Signaling Regulates the Inflammatory Response in an α-Synuclein Model of Parkinson Disease |
title | Fractalkine Signaling Regulates the Inflammatory Response in an α-Synuclein Model of Parkinson Disease |
title_full | Fractalkine Signaling Regulates the Inflammatory Response in an α-Synuclein Model of Parkinson Disease |
title_fullStr | Fractalkine Signaling Regulates the Inflammatory Response in an α-Synuclein Model of Parkinson Disease |
title_full_unstemmed | Fractalkine Signaling Regulates the Inflammatory Response in an α-Synuclein Model of Parkinson Disease |
title_short | Fractalkine Signaling Regulates the Inflammatory Response in an α-Synuclein Model of Parkinson Disease |
title_sort | fractalkine signaling regulates the inflammatory response in an α-synuclein model of parkinson disease |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4607155/ https://www.ncbi.nlm.nih.gov/pubmed/26469270 http://dx.doi.org/10.1371/journal.pone.0140566 |
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