Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Hass, Ethan W., Sorrentino, Zachary A., Lloyd, Grace M., McFarland, Nikolaus R., Prokop, Stefan, Giasson, Benoit I.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2021
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
_version_ 1783687501309804544
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
work_keys_str_mv AT hassethanw robustasynucleinpathologyinselectbrainstemneuronalpopulationsisapotentialinstigatorofmultiplesystematrophy
AT sorrentinozacharya robustasynucleinpathologyinselectbrainstemneuronalpopulationsisapotentialinstigatorofmultiplesystematrophy
AT lloydgracem robustasynucleinpathologyinselectbrainstemneuronalpopulationsisapotentialinstigatorofmultiplesystematrophy
AT mcfarlandnikolausr robustasynucleinpathologyinselectbrainstemneuronalpopulationsisapotentialinstigatorofmultiplesystematrophy
AT prokopstefan robustasynucleinpathologyinselectbrainstemneuronalpopulationsisapotentialinstigatorofmultiplesystematrophy
AT giassonbenoiti robustasynucleinpathologyinselectbrainstemneuronalpopulationsisapotentialinstigatorofmultiplesystematrophy