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

Area of Science:

• Neuroimmunology
• Genomics
• Cell Biology

Background:

• Multiple sclerosis (MS) exhibits sex-biased incidence, affecting females 3:1 in the USA.
• Males with MS often experience a more severe disease course at diagnosis.
• The underlying causes and consequences of these sex disparities in MS are not fully understood.

Purpose of the Study:

• To investigate sex-based gene expression differences at a cellular level in MS.
• To identify fine-scale sex disparities in gene and pathway expression.
• To explore potential sex-specific therapeutic targets or treatment strategies for MS.

Main Methods:

• Analysis of public single-nuclei RNA-sequencing data from three studies on 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.

Main Results:

• Female MS oligodendrocytes and oligodendrocyte progenitor cells showed distinct expression changes compared to healthy controls, unlike in males.
• Upregulated genes in females included HLA-A in oligodendrocytes and clusterin in oligodendrocyte progenitor cells.
• Several upregulated mitochondrial genes involved in electron transport were observed in female oligodendrocytes and progenitors.

Conclusions:

• Altered states in female oligodendrocyte progenitors and oligodendrocytes suggest sex-specific programming in response to demyelination.
• Increased clusterin and oligodendrocyte progenitor availability in females may indicate enhanced repair and remyelination potential.
• These cellular differences could contribute to the observed sex disparities in MS etiology and disease course.