Sex differences in progressive multiple sclerosis brain gene expression in oligodendrocytes and OPCs

Abstract

Multiple sclerosis is a neurological autoimmune disease with sex-imbalanced incidence; in the USA, the disease is more likely to effect females at a ratio of 3:1. In addition, males are more likely to have a more severe disease course at time of diagnosis. Questions about both causes and downstream effects of this disparity remain. We aim to investigate gene expression differences at a cellular level while considering sex to discover fine-scale sex disparities. These investigations could provide new avenues for treatment targeting, or treatment planning based on sex. Public single-nuclei RNA-sequencing data from three publications of progressive MS including control brains were analysed using the Seurat R package. Differential gene and pathway expression was looked at both within a specific data set which has sub-lesion level sample dissection and across all studies to provide a broader lens. This allowed for the consideration of cell types and spatial positioning in relation to the interrogated lesion in some of the calculations. Our analysis showed expression changes in the female MS oligodendrocytes and oligodendrocyte progenitor cells compared to healthy controls, which were not observed in the corresponding male affected cells. Differentially up-regulated genes in females include increased HLA-A in the oligodendrocytes, and increased clusterin in the oligodendrocyte progenitor cells. There are also several mitochondrial genes in both the oligodendrocytes and oligodendrocyte progenitors which are up-regulated in females, including several directly involved in electron transport and which have previously been associated with neurodegenerative diseases. These results point to altered states in oligodendrocyte progenitors and oligodendrocytes that in combination with known physiological dissimilarities between sexes may denote different programming in males and females in response to the onset of demyelinating lesions. The potential for increased debris clearance mediated by clusterin and availability of oligodendrocyte progenitors in females may indicate an environment more primed for repair, potentially including remyelination. This could contribute to the disparity in etiology in females versus males.

Keywords: Multiple sclerosis; OPCs; oligodendrocytes; remyelination; sex-specific; snRNA-seq.

Figure 1.. Genes which are differentially expressed in each cell subset.

Genes represented are all those that were significant in male Oligos and female OPCs; this data is a subset of the data shown in the heatmap in Supplemental Figure 1; includes all genes which were significant in male OLs and female OPCs

Figure 2.. Heatmap of HLA-A transcription in OLs and CD8+ T localization by region examined in Absinta et al. data.

For the OLs, transcripts and cells for each region were counted, and plotted values are count of transcripts divided by number of cells for each region. For CD8+ T cells, plotted values indicate number of cells identified in each region. Dark blue indicates lower values, light blue indicates higher values. NBT – normal-appearing brain tissue

Figure 3.. Relative expression by sex of MBP, PLP1, OLIG1 and NG2 in OLs and OPCs across lesion regions compared to CLU expression from all cells across lesion regions in Absinta et al. data.

NBT – normal-appearing brain tissue