RETRACTED ARTICLE: Unique RNA signature of different lesion types in the brain white matter in progressive multiple sclerosis

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. Electronic supplementary material The online version of this article (10.1186/s40478-019-0709-3) contains supplementary material, which is available to authorized users.

Proteomic changes during experimental de- and remyelination in the corpus callosum

“…In early remyelination, two of them were upregulated and the other six members not affected significantly, while the reverse pattern was observed during late remyelination ( Fig 5A). We searched occurrence of the eight genes among genes expressed differentially between human multiple sclerosis lesion types vs. NAWM [20]. As we found, four of them were differentially expressed in at least one of the lesion types, and perlecan (HSPG2) gene was the most upregulated in remyelinating lesions (Fig 5B).…”

“…Differential expression of IPA predicted regulatory genes among human multiple sclerosis lesion types vs. nonaffected white matter (NAWM) was identified by using the edgeR package (3.8) software [19] from the database created previously [20]. Adjusted p value filtering using the procedure of Benjamini and Hochberg was used to establish significant differences.…”

“…The resulting network is presented (A). Occurrence of the network orthologues among genes expressed differentially between human multiple sclerosis lesion types vs. NAWM [20] was studied by using the edgeR package (3.8) software [19]. The results are presented as a heat map.…”

Molecular signature of different lesion types in the brain white matter of patients with progressive multiple sclerosis

“…Two recent studies have performed nuclei-RNA sequencing on MS WM tissue; however, their focus have been on specific cell types, i.e. neurons and oligodendrocytes [39, 74] We performed bulk RNA sequencing that neglects the cell type but major strengths are high coverage from a high number of samples, and analysis of nuclear, cytoplasmic and extracellular RNA both coding and non-coding [19]. Here, we have re-analyzed the data from our original study, since we discovered that a bug in the analysis scripts resulted in incorrect label annotation files for 10 out of the 100 samples [20].…”

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

“…The authors have retracted this article [1] because a line was omitted from the data sheet; this was due to a bug in the analysis scripts. This resulted in shifting labels, and incorrect label annotation files for 10 out of 100 samples.…”