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Robust α-synuclein pathology in select brainstem neuronal populations is a potential instigator of multiple system atrophy
Multiple system atrophy (MSA) is an insidious middle age-onset neurodegenerative disease that clinically presents with variable degrees of parkinsonism and cerebellar ataxia. The pathological hallmark of MSA is the progressive accumulation of glial cytoplasmic inclusions (GCIs) in oligodendrocytes t...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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BioMed Central
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8091528/ https://www.ncbi.nlm.nih.gov/pubmed/33941284 http://dx.doi.org/10.1186/s40478-021-01173-y |
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author | Hass, Ethan W. Sorrentino, Zachary A. Lloyd, Grace M. McFarland, Nikolaus R. Prokop, Stefan Giasson, Benoit I. |
author_facet | Hass, Ethan W. Sorrentino, Zachary A. Lloyd, Grace M. McFarland, Nikolaus R. Prokop, Stefan Giasson, Benoit I. |
author_sort | Hass, Ethan W. |
collection | PubMed |
description | Multiple system atrophy (MSA) is an insidious middle age-onset neurodegenerative disease that clinically presents with variable degrees of parkinsonism and cerebellar ataxia. The pathological hallmark of MSA is the progressive accumulation of glial cytoplasmic inclusions (GCIs) in oligodendrocytes that are comprised of α-synuclein (αSyn) aberrantly polymerized into fibrils. Experimentally, MSA brain samples display a high level of seeding activity to induce further αSyn aggregation by a prion-like conformational mechanism. Paradoxically, αSyn is predominantly a neuronal brain protein, with only marginal levels expressed in normal or diseased oligodendrocytes, and αSyn inclusions in other neurodegenerative diseases, including Parkinson’s disease and Dementia with Lewy bodies, are primarily found in neurons. Although GCIs are the hallmark of MSA, using a series of new monoclonal antibodies targeting the carboxy-terminal region of αSyn, we demonstrate that neuronal αSyn pathology in MSA patient brains is remarkably abundant in the pontine nuclei and medullary inferior olivary nucleus. This neuronal αSyn pathology has distinct histological properties compared to GCIs, which allows it to remain concealed to many routine detection methods associated with altered biochemical properties of the carboxy-terminal domain of αSyn. We propose that these previously underappreciated sources of aberrant αSyn could serve as a pool of αSyn prion seeds that can initiate and continue to drive the pathogenesis of MSA. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40478-021-01173-y. |
format | Online Article Text |
id | pubmed-8091528 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-80915282021-05-04 Robust α-synuclein pathology in select brainstem neuronal populations is a potential instigator of multiple system atrophy Hass, Ethan W. Sorrentino, Zachary A. Lloyd, Grace M. McFarland, Nikolaus R. Prokop, Stefan Giasson, Benoit I. Acta Neuropathol Commun Research Multiple system atrophy (MSA) is an insidious middle age-onset neurodegenerative disease that clinically presents with variable degrees of parkinsonism and cerebellar ataxia. The pathological hallmark of MSA is the progressive accumulation of glial cytoplasmic inclusions (GCIs) in oligodendrocytes that are comprised of α-synuclein (αSyn) aberrantly polymerized into fibrils. Experimentally, MSA brain samples display a high level of seeding activity to induce further αSyn aggregation by a prion-like conformational mechanism. Paradoxically, αSyn is predominantly a neuronal brain protein, with only marginal levels expressed in normal or diseased oligodendrocytes, and αSyn inclusions in other neurodegenerative diseases, including Parkinson’s disease and Dementia with Lewy bodies, are primarily found in neurons. Although GCIs are the hallmark of MSA, using a series of new monoclonal antibodies targeting the carboxy-terminal region of αSyn, we demonstrate that neuronal αSyn pathology in MSA patient brains is remarkably abundant in the pontine nuclei and medullary inferior olivary nucleus. This neuronal αSyn pathology has distinct histological properties compared to GCIs, which allows it to remain concealed to many routine detection methods associated with altered biochemical properties of the carboxy-terminal domain of αSyn. We propose that these previously underappreciated sources of aberrant αSyn could serve as a pool of αSyn prion seeds that can initiate and continue to drive the pathogenesis of MSA. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40478-021-01173-y. BioMed Central 2021-05-03 /pmc/articles/PMC8091528/ /pubmed/33941284 http://dx.doi.org/10.1186/s40478-021-01173-y Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/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/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Hass, Ethan W. Sorrentino, Zachary A. Lloyd, Grace M. McFarland, Nikolaus R. Prokop, Stefan Giasson, Benoit I. Robust α-synuclein pathology in select brainstem neuronal populations is a potential instigator of multiple system atrophy |
title | Robust α-synuclein pathology in select brainstem neuronal populations is a potential instigator of multiple system atrophy |
title_full | Robust α-synuclein pathology in select brainstem neuronal populations is a potential instigator of multiple system atrophy |
title_fullStr | Robust α-synuclein pathology in select brainstem neuronal populations is a potential instigator of multiple system atrophy |
title_full_unstemmed | Robust α-synuclein pathology in select brainstem neuronal populations is a potential instigator of multiple system atrophy |
title_short | Robust α-synuclein pathology in select brainstem neuronal populations is a potential instigator of multiple system atrophy |
title_sort | robust α-synuclein pathology in select brainstem neuronal populations is a potential instigator of multiple system atrophy |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8091528/ https://www.ncbi.nlm.nih.gov/pubmed/33941284 http://dx.doi.org/10.1186/s40478-021-01173-y |
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