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Progressive striatonigral degeneration in a transgenic mouse model of multiple system atrophy: translational implications for interventional therapies
Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disorder characterized by widespread oligodendroglial cytoplasmic inclusions of filamentous α-synuclein, and neuronal loss in autonomic centres, basal ganglia and cerebellar circuits. It has been suggested that primary oligoden...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5753576/ https://www.ncbi.nlm.nih.gov/pubmed/29298733 http://dx.doi.org/10.1186/s40478-017-0504-y |
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author | Refolo, Violetta Bez, Francesco Polissidis, Alexia Kuzdas-Wood, Daniela Sturm, Edith Kamaratou, Martina Poewe, Werner Stefanis, Leonidas Angela Cenci, M. Romero-Ramos, Marina Wenning, Gregor K. Stefanova, Nadia |
author_facet | Refolo, Violetta Bez, Francesco Polissidis, Alexia Kuzdas-Wood, Daniela Sturm, Edith Kamaratou, Martina Poewe, Werner Stefanis, Leonidas Angela Cenci, M. Romero-Ramos, Marina Wenning, Gregor K. Stefanova, Nadia |
author_sort | Refolo, Violetta |
collection | PubMed |
description | Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disorder characterized by widespread oligodendroglial cytoplasmic inclusions of filamentous α-synuclein, and neuronal loss in autonomic centres, basal ganglia and cerebellar circuits. It has been suggested that primary oligodendroglial α-synucleinopathy may represent a trigger in the pathogenesis of MSA, but the mechanisms underlying selective vulnerability and disease progression are unclear. The post-mortem analysis of MSA brains provides a static final picture of the disease neuropathology, but gives no clear indication on the sequence of pathogenic events in MSA. Therefore, alternative methods are needed to address these issues. We investigated selective vulnerability and disease progression in the transgenic PLP-α-syn mouse model of MSA characterized by targeted oligodendroglial α-synuclein overexpression aiming to provide a neuropathological correlate of motor deterioration. We show progressive motor deficits that emerge at 6 months of age and deteriorate up to 18 months of follow-up. The motor phenotype was associated with dopaminergic cell loss in the substantia nigra pars compacta at 6 months, followed by loss of striatal dopaminergic terminals and DARPP32-positive medium sized projection neurons at 12 months. Olivopontocerebellar motor loops remained spared in the PLP-α-syn model of MSA. These findings replicate progressive striatonigral degeneration underlying Parkinson-variant MSA. The initiation of the degenerative process was linked to an increase of soluble oligomeric α-synuclein species between 2 and 6 months. Early region-specific α-synuclein-associated activation profile of microglia was found in MSA substantia nigra. The role of abnormal neuroinflammatory signalling in disease progression was further supported by increased levels of CD68, CCL3, CCL5 and M-CSF with a peak in aged PLP-α-syn mice. In summary, transgenic PLP-α-syn mice show a distinctive oligodendroglial α-synucleinopathy that is associated with progressive striatonigral degeneration linked to abnormal neuroinflammatory response. The model provides a relevant tool for preclinical therapeutic target discovery for human Parkinson-variant MSA. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s40478-017-0504-y) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-5753576 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-57535762018-01-08 Progressive striatonigral degeneration in a transgenic mouse model of multiple system atrophy: translational implications for interventional therapies Refolo, Violetta Bez, Francesco Polissidis, Alexia Kuzdas-Wood, Daniela Sturm, Edith Kamaratou, Martina Poewe, Werner Stefanis, Leonidas Angela Cenci, M. Romero-Ramos, Marina Wenning, Gregor K. Stefanova, Nadia Acta Neuropathol Commun Research Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disorder characterized by widespread oligodendroglial cytoplasmic inclusions of filamentous α-synuclein, and neuronal loss in autonomic centres, basal ganglia and cerebellar circuits. It has been suggested that primary oligodendroglial α-synucleinopathy may represent a trigger in the pathogenesis of MSA, but the mechanisms underlying selective vulnerability and disease progression are unclear. The post-mortem analysis of MSA brains provides a static final picture of the disease neuropathology, but gives no clear indication on the sequence of pathogenic events in MSA. Therefore, alternative methods are needed to address these issues. We investigated selective vulnerability and disease progression in the transgenic PLP-α-syn mouse model of MSA characterized by targeted oligodendroglial α-synuclein overexpression aiming to provide a neuropathological correlate of motor deterioration. We show progressive motor deficits that emerge at 6 months of age and deteriorate up to 18 months of follow-up. The motor phenotype was associated with dopaminergic cell loss in the substantia nigra pars compacta at 6 months, followed by loss of striatal dopaminergic terminals and DARPP32-positive medium sized projection neurons at 12 months. Olivopontocerebellar motor loops remained spared in the PLP-α-syn model of MSA. These findings replicate progressive striatonigral degeneration underlying Parkinson-variant MSA. The initiation of the degenerative process was linked to an increase of soluble oligomeric α-synuclein species between 2 and 6 months. Early region-specific α-synuclein-associated activation profile of microglia was found in MSA substantia nigra. The role of abnormal neuroinflammatory signalling in disease progression was further supported by increased levels of CD68, CCL3, CCL5 and M-CSF with a peak in aged PLP-α-syn mice. In summary, transgenic PLP-α-syn mice show a distinctive oligodendroglial α-synucleinopathy that is associated with progressive striatonigral degeneration linked to abnormal neuroinflammatory response. The model provides a relevant tool for preclinical therapeutic target discovery for human Parkinson-variant MSA. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s40478-017-0504-y) contains supplementary material, which is available to authorized users. BioMed Central 2018-01-03 /pmc/articles/PMC5753576/ /pubmed/29298733 http://dx.doi.org/10.1186/s40478-017-0504-y Text en © The Author(s). 2018 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 Refolo, Violetta Bez, Francesco Polissidis, Alexia Kuzdas-Wood, Daniela Sturm, Edith Kamaratou, Martina Poewe, Werner Stefanis, Leonidas Angela Cenci, M. Romero-Ramos, Marina Wenning, Gregor K. Stefanova, Nadia Progressive striatonigral degeneration in a transgenic mouse model of multiple system atrophy: translational implications for interventional therapies |
title | Progressive striatonigral degeneration in a transgenic mouse model of multiple system atrophy: translational implications for interventional therapies |
title_full | Progressive striatonigral degeneration in a transgenic mouse model of multiple system atrophy: translational implications for interventional therapies |
title_fullStr | Progressive striatonigral degeneration in a transgenic mouse model of multiple system atrophy: translational implications for interventional therapies |
title_full_unstemmed | Progressive striatonigral degeneration in a transgenic mouse model of multiple system atrophy: translational implications for interventional therapies |
title_short | Progressive striatonigral degeneration in a transgenic mouse model of multiple system atrophy: translational implications for interventional therapies |
title_sort | progressive striatonigral degeneration in a transgenic mouse model of multiple system atrophy: translational implications for interventional therapies |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5753576/ https://www.ncbi.nlm.nih.gov/pubmed/29298733 http://dx.doi.org/10.1186/s40478-017-0504-y |
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