Unique RNA signature of different lesion types in the brain white matter in progressive multiple sclerosis

Title: Unique RNA signature of different lesion types in the brain white matter in progressive multiple sclerosis
Authors: Elkjaer, ML
Frisch, T
Reynolds, R
Kacprowski, T
Burton, M
Kruse, TA
Thomassen, M
Baumbach, J
Illes, Z
Item Type: Journal Article
Abstract: The heterogeneity of multiple sclerosis is reflected by dynamic changes of different lesion types in the brain white matter (WM). To identify potential drivers of this process, we RNA-sequenced 73 WM areas from patients with progressive MS (PMS) and 25 control WM. Lesion endophenotypes were described by a computational systems medicine analysis combined with RNAscope, immunohistochemistry, and immunofluorescence. The signature of the normal-appearing WM (NAWM) was more similar to control WM than to lesions: one of the six upregulated genes in NAWM was CD26/DPP4 expressed by microglia. Chronic active lesions that become prominent in PMS had a signature that were different from all other lesion types, and were differentiated from them by two clusters of 62 differentially expressed genes (DEGs). An upcoming MS biomarker, CHI3L1 was among the top ten upregulated genes in chronic active lesions expressed by astrocytes in the rim. TGFβ-R2 was the central hub in a remyelination-related protein interaction network, and was expressed there by astrocytes. We used de novo networks enriched by unique DEGs to determine lesion-specific pathway regulation, i.e. cellular trafficking and activation in active lesions; healing and immune responses in remyelinating lesions characterized by the most heterogeneous immunoglobulin gene expression; coagulation and ion balance in inactive lesions; and metabolic changes in chronic active lesions. Because we found inverse differential regulation of particular genes among different lesion types, our data emphasize that omics related to MS lesions should be interpreted in the context of lesion pathology. Our data indicate that the impact of molecular pathways is substantially changing as different lesions develop. This was also reflected by the high number of unique DEGs that were more common than shared signatures. A special microglia subset characterized by CD26 may play a role in early lesion development, while astrocyte-derived TGFβ-R2 and TGFβ pathways may be drivers of repair in contrast to chronic tissue damage. The highly specific mechanistic signature of chronic active lesions indicates that as these lesions develop in PMS, the molecular changes are substantially skewed: the unique mitochondrial/metabolic changes and specific downregulation of molecules involved in tissue repair may reflect a stage of exhaustion.
Issue Date: 25-Apr-2019
Date of Acceptance: 22-Mar-2019
URI: http://hdl.handle.net/10044/1/70346
DOI: https://doi.org/10.1186/s40478-019-0709-3
ISSN: 2051-5960
Publisher: BioMed Central
Journal / Book Title: Acta Neuropathologica Communications
Volume: 7
Issue: 1
Copyright Statement: © 2019 The Author(s). Open Access This 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.
Keywords: Science & Technology
Life Sciences & Biomedicine
Neurosciences
Neurosciences & Neurology
Multiple sclerosis brain lesions
Next-generation RNA sequencing
TGF-beta
Chitinase-3-like protein-1
CD26
DPP4
INFLAMMATION
EXPRESSION
DEMYELINATION
HYPOXIA
NEURODEGENERATION
IMMUNOPATHOLOGY
MECHANISMS
ASTROCYTE
INSIGHTS
PROMOTES
CD26/DPP4
Chitinase-3-like protein-1
Multiple sclerosis brain lesions
Next-generation RNA sequencing
TGF-beta
Science & Technology
Life Sciences & Biomedicine
Neurosciences
Neurosciences & Neurology
Multiple sclerosis brain lesions
Next-generation RNA sequencing
TGF-beta
Chitinase-3-like protein-1
CD26
DPP4
INFLAMMATION
EXPRESSION
DEMYELINATION
HYPOXIA
NEURODEGENERATION
IMMUNOPATHOLOGY
MECHANISMS
ASTROCYTE
INSIGHTS
PROMOTES
Publication Status: Published
Article Number: 58
Online Publication Date: 2019-04-25
Appears in Collections:Department of Medicine



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