Abstract
To identify pathogenetic markers and potential drivers of different lesion types in the white matter (WM) of patients with progressive multiple sclerosis (PMS), we sequenced RNA from 73 different WM areas. Compared to 25 WM controls, 6713 out of 18,609 genes were significantly differentially expressed in MS tissues (FDR < 0.05). A computational systems medicine analysis was performed to describe the MS lesion endophenotypes. The cellular source of specific molecules was examined by RNAscope, immunohistochemistry, and immunofluorescence. To examine common lesion specific mechanisms, we performed de novo network enrichment based on shared differentially expressed genes (DEGs), and found TGFβ-R2 as a central hub. RNAscope revealed astrocytes as the cellular source of TGFβ-R2 in remyelinating lesions. Since lesion-specific unique DEGs were more common than shared signatures, we examined lesion-specific pathways and de novo networks enriched with unique DEGs. Such network analysis indicated classic inflammatory responses in active lesions; catabolic and heat shock protein responses in inactive lesions; neuronal/axonal specific processes in chronic active lesions. In remyelinating lesions, de novo analyses identified axonal transport responses and adaptive immune markers, which was also supported by the most heterogeneous immunoglobulin gene expression. The signature of the normal-appearing white matter (NAWM) was more similar to control WM than to lesions: only 465 DEGs differentiated NAWM from controls, and 16 were unique. The upregulated marker CD26/DPP4 was expressed by microglia in the NAWM but by mononuclear cells in active lesions, which may indicate a special subset of microglia before the lesion develops, but also emphasizes that omics related to MS lesions should be interpreted in the context of different lesions types. While chronic active lesions were the most distinct from control WM based on the highest number of unique DEGs (n = 2213), remyelinating lesions had the highest gene expression levels, and the most different molecular map from chronic active lesions. This may suggest that these two lesion types represent two ends of the spectrum of lesion evolution in PMS. The profound changes in chronic active lesions, the predominance of synaptic/neural/axonal signatures coupled with minor inflammation may indicate end-stage irreversible molecular events responsible for this less treatable phase.
Highlights
Multiple sclerosis (MS) is a chronic inflammatory, demyelinating and neurodegenerative disease of the CNS
In the normal-appearing white matter (NAWM), only 465 differentially expressed genes (DEGs) were present, and the highest number of DEGs was found in chronic active lesions (Fig. 2b)
Transcriptome changes specific to different lesion types In order to investigate unique transcriptional changes at different stages of lesion evolution and fate, we applied a comprehensive approach: (i) we identified DEGs that were differentially regulated at least among two lesion types visualized in a global transcriptome heatmap (Fig. 4); (ii) we investigated predefined pathways based on DEGs that were present only in one lesion type (Fig. 5); (iii) we extracted unique significant (FDR < 0.001) upand downregulated genes in each lesion type, and created de novo enriched protein interaction networks with major hubs for these DEGs (Fig. 6)
Summary
Multiple sclerosis (MS) is a chronic inflammatory, demyelinating and neurodegenerative disease of the CNS. A secondary progressive course (SPMS) develops in about half of the patients [65]. Neuroimaging, treatment responses and pathology all show differences between the early and late phase of MS, indicating that disease mechanisms change during the natural course [31]. Inflammatory demyelination affects osmotic homeostasis, energy coupling with oligodendrocytes, and contributes to glutamate excitotoxicity, axonal damage and fibrillary gliosis that may inhibit remyelination [23, 49]. Diffuse changes can be observed in the normal appearing white and grey matter (NAWM, NAGM), and B cell follicle-like cellular aggregates in the meninges contribute to subpial cortical lesions [48, 59, 72]
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