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Insights into the pathogenesis of multiple system atrophy: focus on glial cytoplasmic inclusions

Multiple system atrophy (MSA) is a debilitating and fatal neurodegenerative disorder. The disease severity warrants urgent development of disease-modifying therapy, but the disease pathogenesis is still enigmatic. Neurodegeneration in MSA brains is preceded by the emergence of glial cytoplasmic incl...

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Autores principales: Kaji, Seiji, Maki, Takakuni, Ishimoto, Tomoyuki, Yamakado, Hodaka, Takahashi, Ryosuke
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7025408/
https://www.ncbi.nlm.nih.gov/pubmed/32095235
http://dx.doi.org/10.1186/s40035-020-0185-5
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author Kaji, Seiji
Maki, Takakuni
Ishimoto, Tomoyuki
Yamakado, Hodaka
Takahashi, Ryosuke
author_facet Kaji, Seiji
Maki, Takakuni
Ishimoto, Tomoyuki
Yamakado, Hodaka
Takahashi, Ryosuke
author_sort Kaji, Seiji
collection PubMed
description Multiple system atrophy (MSA) is a debilitating and fatal neurodegenerative disorder. The disease severity warrants urgent development of disease-modifying therapy, but the disease pathogenesis is still enigmatic. Neurodegeneration in MSA brains is preceded by the emergence of glial cytoplasmic inclusions (GCIs), which are insoluble α-synuclein accumulations within oligodendrocytes (OLGs). Thus, preventive strategies against GCI formation may suppress disease progression. However, although numerous studies have tried to elucidate the molecular pathogenesis of GCI formation, difficulty remains in understanding the pathological interaction between the two pivotal aspects of GCIs; α-synuclein and OLGs. The difficulty originates from several enigmas: 1) what triggers the initial generation and possible propagation of pathogenic α-synuclein species? 2) what contributes to OLG-specific accumulation of α-synuclein, which is abundantly expressed in neurons but not in OLGs? and 3) how are OLGs and other glial cells affected and contribute to neurodegeneration? The primary pathogenesis of GCIs may involve myelin dysfunction and dyshomeostasis of the oligodendroglial cellular environment such as autophagy and iron metabolism. We have previously reported that oligodendrocyte precursor cells are more prone to develop intracellular inclusions in the presence of extracellular fibrillary α-synuclein. This finding implies a possibility that the propagation of GCI pathology in MSA brains is mediated through the internalization of pathological α-synuclein into oligodendrocyte precursor cells. In this review, in order to discuss the pathogenesis of GCIs, we will focus on the composition of neuronal and oligodendroglial inclusions in synucleinopathies. Furthermore, we will introduce some hypotheses on how α-synuclein pathology spreads among OLGs in MSA brains, in the light of our data from the experiments with primary oligodendrocyte lineage cell culture. While various reports have focused on the mysterious source of α-synuclein in GCIs, insights into the mechanism which regulates the uptake of pathological α-synuclein into oligodendroglial cells may yield the development of the disease-modifying therapy for MSA. The interaction between glial cells and α-synuclein is also highlighted with previous studies of post-mortem human brains, cultured cells, and animal models, which provide comprehensive insight into GCIs and the MSA pathomechanisms.
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spelling pubmed-70254082020-02-24 Insights into the pathogenesis of multiple system atrophy: focus on glial cytoplasmic inclusions Kaji, Seiji Maki, Takakuni Ishimoto, Tomoyuki Yamakado, Hodaka Takahashi, Ryosuke Transl Neurodegener Review Multiple system atrophy (MSA) is a debilitating and fatal neurodegenerative disorder. The disease severity warrants urgent development of disease-modifying therapy, but the disease pathogenesis is still enigmatic. Neurodegeneration in MSA brains is preceded by the emergence of glial cytoplasmic inclusions (GCIs), which are insoluble α-synuclein accumulations within oligodendrocytes (OLGs). Thus, preventive strategies against GCI formation may suppress disease progression. However, although numerous studies have tried to elucidate the molecular pathogenesis of GCI formation, difficulty remains in understanding the pathological interaction between the two pivotal aspects of GCIs; α-synuclein and OLGs. The difficulty originates from several enigmas: 1) what triggers the initial generation and possible propagation of pathogenic α-synuclein species? 2) what contributes to OLG-specific accumulation of α-synuclein, which is abundantly expressed in neurons but not in OLGs? and 3) how are OLGs and other glial cells affected and contribute to neurodegeneration? The primary pathogenesis of GCIs may involve myelin dysfunction and dyshomeostasis of the oligodendroglial cellular environment such as autophagy and iron metabolism. We have previously reported that oligodendrocyte precursor cells are more prone to develop intracellular inclusions in the presence of extracellular fibrillary α-synuclein. This finding implies a possibility that the propagation of GCI pathology in MSA brains is mediated through the internalization of pathological α-synuclein into oligodendrocyte precursor cells. In this review, in order to discuss the pathogenesis of GCIs, we will focus on the composition of neuronal and oligodendroglial inclusions in synucleinopathies. Furthermore, we will introduce some hypotheses on how α-synuclein pathology spreads among OLGs in MSA brains, in the light of our data from the experiments with primary oligodendrocyte lineage cell culture. While various reports have focused on the mysterious source of α-synuclein in GCIs, insights into the mechanism which regulates the uptake of pathological α-synuclein into oligodendroglial cells may yield the development of the disease-modifying therapy for MSA. The interaction between glial cells and α-synuclein is also highlighted with previous studies of post-mortem human brains, cultured cells, and animal models, which provide comprehensive insight into GCIs and the MSA pathomechanisms. BioMed Central 2020-02-17 /pmc/articles/PMC7025408/ /pubmed/32095235 http://dx.doi.org/10.1186/s40035-020-0185-5 Text en © The Author(s). 2020 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 Review
Kaji, Seiji
Maki, Takakuni
Ishimoto, Tomoyuki
Yamakado, Hodaka
Takahashi, Ryosuke
Insights into the pathogenesis of multiple system atrophy: focus on glial cytoplasmic inclusions
title Insights into the pathogenesis of multiple system atrophy: focus on glial cytoplasmic inclusions
title_full Insights into the pathogenesis of multiple system atrophy: focus on glial cytoplasmic inclusions
title_fullStr Insights into the pathogenesis of multiple system atrophy: focus on glial cytoplasmic inclusions
title_full_unstemmed Insights into the pathogenesis of multiple system atrophy: focus on glial cytoplasmic inclusions
title_short Insights into the pathogenesis of multiple system atrophy: focus on glial cytoplasmic inclusions
title_sort insights into the pathogenesis of multiple system atrophy: focus on glial cytoplasmic inclusions
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7025408/
https://www.ncbi.nlm.nih.gov/pubmed/32095235
http://dx.doi.org/10.1186/s40035-020-0185-5
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