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Cortical Pathology in Vanishing White Matter

Vanishing white matter (VWM) is classified as a leukodystrophy with astrocytes as primary drivers in its pathogenesis. Magnetic resonance imaging has documented the progressive thinning of cortices in long-surviving patients. Routine histopathological analyses, however, have not yet pointed to corti...

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Autores principales: Man, Jodie H. K., van Gelder, Charlotte A. G. H., Breur, Marjolein, Okkes, Daniel, Molenaar, Douwe, van der Sluis, Sophie, Abbink, Truus, Altelaar, Maarten, van der Knaap, Marjo S., Bugiani, Marianna
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9688115/
https://www.ncbi.nlm.nih.gov/pubmed/36429009
http://dx.doi.org/10.3390/cells11223581
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author Man, Jodie H. K.
van Gelder, Charlotte A. G. H.
Breur, Marjolein
Okkes, Daniel
Molenaar, Douwe
van der Sluis, Sophie
Abbink, Truus
Altelaar, Maarten
van der Knaap, Marjo S.
Bugiani, Marianna
author_facet Man, Jodie H. K.
van Gelder, Charlotte A. G. H.
Breur, Marjolein
Okkes, Daniel
Molenaar, Douwe
van der Sluis, Sophie
Abbink, Truus
Altelaar, Maarten
van der Knaap, Marjo S.
Bugiani, Marianna
author_sort Man, Jodie H. K.
collection PubMed
description Vanishing white matter (VWM) is classified as a leukodystrophy with astrocytes as primary drivers in its pathogenesis. Magnetic resonance imaging has documented the progressive thinning of cortices in long-surviving patients. Routine histopathological analyses, however, have not yet pointed to cortical involvement in VWM. Here, we provide a comprehensive analysis of the VWM cortex. We employed high-resolution-mass-spectrometry-based proteomics and immunohistochemistry to gain insight into possible molecular disease mechanisms in the cortices of VWM patients. The proteome analysis revealed 268 differentially expressed proteins in the VWM cortices compared to the controls. A majority of these proteins formed a major protein interaction network. A subsequent gene ontology analysis identified enrichment for terms such as cellular metabolism, particularly mitochondrial activity. Importantly, some of the proteins with the most prominent changes in expression were found in astrocytes, indicating cortical astrocytic involvement. Indeed, we confirmed that VWM cortical astrocytes exhibit morphological changes and are less complex in structure than control cells. Our findings also suggest that these astrocytes are immature and not reactive. Taken together, we provide insights into cortical involvement in VWM, which has to be taken into account when developing therapeutic strategies.
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spelling pubmed-96881152022-11-25 Cortical Pathology in Vanishing White Matter Man, Jodie H. K. van Gelder, Charlotte A. G. H. Breur, Marjolein Okkes, Daniel Molenaar, Douwe van der Sluis, Sophie Abbink, Truus Altelaar, Maarten van der Knaap, Marjo S. Bugiani, Marianna Cells Article Vanishing white matter (VWM) is classified as a leukodystrophy with astrocytes as primary drivers in its pathogenesis. Magnetic resonance imaging has documented the progressive thinning of cortices in long-surviving patients. Routine histopathological analyses, however, have not yet pointed to cortical involvement in VWM. Here, we provide a comprehensive analysis of the VWM cortex. We employed high-resolution-mass-spectrometry-based proteomics and immunohistochemistry to gain insight into possible molecular disease mechanisms in the cortices of VWM patients. The proteome analysis revealed 268 differentially expressed proteins in the VWM cortices compared to the controls. A majority of these proteins formed a major protein interaction network. A subsequent gene ontology analysis identified enrichment for terms such as cellular metabolism, particularly mitochondrial activity. Importantly, some of the proteins with the most prominent changes in expression were found in astrocytes, indicating cortical astrocytic involvement. Indeed, we confirmed that VWM cortical astrocytes exhibit morphological changes and are less complex in structure than control cells. Our findings also suggest that these astrocytes are immature and not reactive. Taken together, we provide insights into cortical involvement in VWM, which has to be taken into account when developing therapeutic strategies. MDPI 2022-11-12 /pmc/articles/PMC9688115/ /pubmed/36429009 http://dx.doi.org/10.3390/cells11223581 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Man, Jodie H. K.
van Gelder, Charlotte A. G. H.
Breur, Marjolein
Okkes, Daniel
Molenaar, Douwe
van der Sluis, Sophie
Abbink, Truus
Altelaar, Maarten
van der Knaap, Marjo S.
Bugiani, Marianna
Cortical Pathology in Vanishing White Matter
title Cortical Pathology in Vanishing White Matter
title_full Cortical Pathology in Vanishing White Matter
title_fullStr Cortical Pathology in Vanishing White Matter
title_full_unstemmed Cortical Pathology in Vanishing White Matter
title_short Cortical Pathology in Vanishing White Matter
title_sort cortical pathology in vanishing white matter
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9688115/
https://www.ncbi.nlm.nih.gov/pubmed/36429009
http://dx.doi.org/10.3390/cells11223581
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