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T cell infiltration in both human multiple system atrophy and a novel mouse model of the disease
Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by abnormal accumulation of alpha-synuclein (α-syn) in oligodendrocytes accompanied by inflammation, demyelination, and subsequent synapse and neuronal loss. Little is known about the mechanisms of neurodegenerat...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Berlin Heidelberg
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181566/ https://www.ncbi.nlm.nih.gov/pubmed/31993745 http://dx.doi.org/10.1007/s00401-020-02126-w |
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author | Williams, Gregory P. Marmion, David J. Schonhoff, Aubrey M. Jurkuvenaite, Asta Won, Woong-Jai Standaert, David G. Kordower, Jeffrey H. Harms, Ashley S. |
author_facet | Williams, Gregory P. Marmion, David J. Schonhoff, Aubrey M. Jurkuvenaite, Asta Won, Woong-Jai Standaert, David G. Kordower, Jeffrey H. Harms, Ashley S. |
author_sort | Williams, Gregory P. |
collection | PubMed |
description | Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by abnormal accumulation of alpha-synuclein (α-syn) in oligodendrocytes accompanied by inflammation, demyelination, and subsequent synapse and neuronal loss. Little is known about the mechanisms of neurodegeneration in MSA. However, recent work has highlighted the important role of the immune system to the pathophysiology of other synuclein-related diseases such as Parkinson’s disease. In this study, we investigated postmortem brain tissue from MSA patients and control subjects for evidence of immune activation in the brain. We found a significant increase of HLA-DR(+) microglia in the putamen and substantia nigra of MSA patient tissue compared to controls, as well as significant increases in CD3(+), CD4(+), and CD8(+) T cells in these same brain regions. To model MSA in vivo, we utilized a viral vector that selectively overexpresses α-syn in oligodendrocytes (Olig001-SYN) with > 95% tropism in the dorsal striatum of mice, resulting in demyelination and neuroinflammation similar to that observed in human MSA. Oligodendrocyte transduction with this vector resulted in a robust inflammatory response, which included increased MHCII expression on central nervous system (CNS) resident microglia, and infiltration of pro-inflammatory monocytes into the CNS. We also observed robust infiltration of CD4 T cells into the CNS and antigen-experienced CD4 T cells in the draining cervical lymph nodes. Importantly, genetic deletion of TCR-β or CD4 T cells attenuated α-syn-induced inflammation and demyelination in vivo. These results suggest that T cell priming and infiltration into the CNS are key mechanisms of disease pathogenesis in MSA, and therapeutics targeting T cells may be disease modifying. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00401-020-02126-w) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-7181566 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Springer Berlin Heidelberg |
record_format | MEDLINE/PubMed |
spelling | pubmed-71815662020-04-29 T cell infiltration in both human multiple system atrophy and a novel mouse model of the disease Williams, Gregory P. Marmion, David J. Schonhoff, Aubrey M. Jurkuvenaite, Asta Won, Woong-Jai Standaert, David G. Kordower, Jeffrey H. Harms, Ashley S. Acta Neuropathol Original Paper Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by abnormal accumulation of alpha-synuclein (α-syn) in oligodendrocytes accompanied by inflammation, demyelination, and subsequent synapse and neuronal loss. Little is known about the mechanisms of neurodegeneration in MSA. However, recent work has highlighted the important role of the immune system to the pathophysiology of other synuclein-related diseases such as Parkinson’s disease. In this study, we investigated postmortem brain tissue from MSA patients and control subjects for evidence of immune activation in the brain. We found a significant increase of HLA-DR(+) microglia in the putamen and substantia nigra of MSA patient tissue compared to controls, as well as significant increases in CD3(+), CD4(+), and CD8(+) T cells in these same brain regions. To model MSA in vivo, we utilized a viral vector that selectively overexpresses α-syn in oligodendrocytes (Olig001-SYN) with > 95% tropism in the dorsal striatum of mice, resulting in demyelination and neuroinflammation similar to that observed in human MSA. Oligodendrocyte transduction with this vector resulted in a robust inflammatory response, which included increased MHCII expression on central nervous system (CNS) resident microglia, and infiltration of pro-inflammatory monocytes into the CNS. We also observed robust infiltration of CD4 T cells into the CNS and antigen-experienced CD4 T cells in the draining cervical lymph nodes. Importantly, genetic deletion of TCR-β or CD4 T cells attenuated α-syn-induced inflammation and demyelination in vivo. These results suggest that T cell priming and infiltration into the CNS are key mechanisms of disease pathogenesis in MSA, and therapeutics targeting T cells may be disease modifying. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00401-020-02126-w) contains supplementary material, which is available to authorized users. Springer Berlin Heidelberg 2020-01-29 2020 /pmc/articles/PMC7181566/ /pubmed/31993745 http://dx.doi.org/10.1007/s00401-020-02126-w Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Original Paper Williams, Gregory P. Marmion, David J. Schonhoff, Aubrey M. Jurkuvenaite, Asta Won, Woong-Jai Standaert, David G. Kordower, Jeffrey H. Harms, Ashley S. T cell infiltration in both human multiple system atrophy and a novel mouse model of the disease |
title | T cell infiltration in both human multiple system atrophy and a novel mouse model of the disease |
title_full | T cell infiltration in both human multiple system atrophy and a novel mouse model of the disease |
title_fullStr | T cell infiltration in both human multiple system atrophy and a novel mouse model of the disease |
title_full_unstemmed | T cell infiltration in both human multiple system atrophy and a novel mouse model of the disease |
title_short | T cell infiltration in both human multiple system atrophy and a novel mouse model of the disease |
title_sort | t cell infiltration in both human multiple system atrophy and a novel mouse model of the disease |
topic | Original Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181566/ https://www.ncbi.nlm.nih.gov/pubmed/31993745 http://dx.doi.org/10.1007/s00401-020-02126-w |
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