A Systematic Review of Tissue and Single Cell Transcriptome/Proteome Studies of the Brain in Multiple Sclerosis

Abstract

Multiple sclerosis (MS) is an inflammatory demyelinating and degenerative disease of the central nervous system (CNS). Although inflammatory responses are efficiently treated, therapies for progression are scarce and suboptimal, and biomarkers to predict the disease course are insufficient. Cure or preventive measures for MS require knowledge of core pathological events at the site of the tissue damage. Novelties in systems biology have emerged and paved the way for a more fine-grained understanding of key pathological pathways within the CNS, but they have also raised questions still without answers. Here, we systemically review the power of tissue and single-cell/nucleus CNS omics and discuss major gaps of integration into the clinical practice. Systemic search identified 49 transcriptome and 11 proteome studies of the CNS from 1997 till October 2021. Pioneering molecular discoveries indicate that MS affects the whole brain and all resident cell types. Despite inconsistency of results, studies imply increase in transcripts/proteins of semaphorins, heat shock proteins, myelin proteins, apolipoproteins and HLAs. Different lesions are characterized by distinct astrocytic and microglial polarization, altered oligodendrogenesis, and changes in specific neuronal subtypes. In all white matter lesion types, CXCL12, SCD, CD163 are highly expressed, and STAT6- and TGFβ-signaling are increased. In the grey matter lesions, TNF-signaling seems to drive cell death, and especially CUX2-expressing neurons may be susceptible to neurodegeneration. The vast heterogeneity at both cellular and lesional levels may underlie the clinical heterogeneity of MS, and it may be more complex than the current disease phenotyping in the clinical practice. Systems biology has not solved the mystery of MS, but it has discovered multiple molecules and networks potentially contributing to the pathogenesis. However, these results are mostly descriptive; focused functional studies of the molecular changes may open up for a better interpretation. Guidelines for acceptable quality or awareness of results from low quality data, and standardized computational and biological pipelines may help to overcome limited tissue availability and the “snap shot” problem of omics. These may help in identifying core pathological events and point in directions for focus in clinical prevention.

Identification of Key Genes and Regulatory Pathways in Multiple Sclerosis Brain Samples: A Meta-Analysis of Micro-Array Datasets

“…Therefore, results from our bioinformatics approach further confirmed such alterations of these biological processes in human ex vivo MS WM tissues. Similarly, a systematic review of proteomic studies reported several imbalances of WM proteostasis in MS brains [38], as seen in our study, although these reports showed some inconsistencies that were most likely due to the clinical heterogeneity of the disease. KEGG analyses also revealed alterations in pathways associated with insulin resistance.…”

Defective Integrator activity shapes the transcriptome of patients with multiple sclerosis

“…pVal<0.05, baseMean>10 -Figure 1F). As an@cipated from earlier studies, pathway analysis using the KEGG database on upregulated genes iden@fied ac@va@on of the IL17-, TGF-beta-, NFkappaB-, and MAPK-pathways as well as genes associated with hypoxia (Elkjaer et al, 2022) (Sup. Figure 1B).…”

Publicly available ex vivo transcriptomics datasets to explore CNS physiology and neurodegeneration: state of the art and perspectives

“…A recent review summarized CNS transcriptomics studies in multiple sclerosis ( Elkjaer et al, 2022 ). For example, RNA-seq of a large number of white matter MS lesions provided molecular profiling for distinct lesion types and identified TGFBR2 as major common hub mostly upregulated in remyelinating lesions ( Elkjaer et al, 2019 ; Table 1 , GSE138614).…”