Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2018
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
_version_ 1783290303067717632
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
work_keys_str_mv AT refolovioletta progressivestriatonigraldegenerationinatransgenicmousemodelofmultiplesystematrophytranslationalimplicationsforinterventionaltherapies
AT bezfrancesco progressivestriatonigraldegenerationinatransgenicmousemodelofmultiplesystematrophytranslationalimplicationsforinterventionaltherapies
AT polissidisalexia progressivestriatonigraldegenerationinatransgenicmousemodelofmultiplesystematrophytranslationalimplicationsforinterventionaltherapies
AT kuzdaswooddaniela progressivestriatonigraldegenerationinatransgenicmousemodelofmultiplesystematrophytranslationalimplicationsforinterventionaltherapies
AT sturmedith progressivestriatonigraldegenerationinatransgenicmousemodelofmultiplesystematrophytranslationalimplicationsforinterventionaltherapies
AT kamaratoumartina progressivestriatonigraldegenerationinatransgenicmousemodelofmultiplesystematrophytranslationalimplicationsforinterventionaltherapies
AT poewewerner progressivestriatonigraldegenerationinatransgenicmousemodelofmultiplesystematrophytranslationalimplicationsforinterventionaltherapies
AT stefanisleonidas progressivestriatonigraldegenerationinatransgenicmousemodelofmultiplesystematrophytranslationalimplicationsforinterventionaltherapies
AT angelacencim progressivestriatonigraldegenerationinatransgenicmousemodelofmultiplesystematrophytranslationalimplicationsforinterventionaltherapies
AT romeroramosmarina progressivestriatonigraldegenerationinatransgenicmousemodelofmultiplesystematrophytranslationalimplicationsforinterventionaltherapies
AT wenninggregork progressivestriatonigraldegenerationinatransgenicmousemodelofmultiplesystematrophytranslationalimplicationsforinterventionaltherapies
AT stefanovanadia progressivestriatonigraldegenerationinatransgenicmousemodelofmultiplesystematrophytranslationalimplicationsforinterventionaltherapies