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

Area of Science:

• Neuroimmunology
• Genomics
• Cellular Biology

Background:

• Multiple sclerosis (MS) exhibits significant sex disparities in incidence and severity.
• Females are diagnosed with MS 3:1 more often than males, who tend to experience a more severe disease course.
• The underlying causes and cellular mechanisms driving these sex differences remain largely unknown.

Purpose of the Study:

• To investigate sex-specific gene expression differences at a cellular level in multiple sclerosis.
• To identify potential molecular mechanisms contributing to the observed sex disparities in MS.
• To explore new avenues for sex-specific treatment targeting and planning in MS.

Main Methods:

• Analysis of public single-nuclei RNA-sequencing data from three studies of progressive MS and control brains.
• Utilized the Seurat R package for differential gene and pathway expression analysis.
• Considered cell types and spatial positioning relative to lesions, including sub-lesion level dissections.

Main Results:

• Observed distinct gene expression changes in oligodendrocytes and oligodendrocyte progenitor cells in female MS patients compared to healthy controls and affected males.
• Identified up-regulation of HLA-A in female oligodendrocytes and clusterin in female oligodendrocyte progenitor cells.
• Found increased expression of mitochondrial genes involved in electron transport in female oligodendrocytes and progenitors, linked to neurodegeneration.

Conclusions:

• Altered gene expression in oligodendrocytes and oligodendrocyte progenitors suggests sex-specific cellular programming in response to MS lesions.
• Upregulation of clusterin in females may enhance debris clearance, and progenitor availability could prime for repair, including remyelination.
• These findings highlight potential sex differences in MS etiology and repair capacity, informing future therapeutic strategies.