Genomics and transcriptomics analysis of multiple sclerosis pathology

Jeen Engelenburg
A new genetic variant associated with age-related multiple sclerosis severity associates with enhanced lesion activity and axonal damage

A recent genome-wide association study of 12,584 people with multiple sclerosis (MS), conducted by the International MS Genetics Consortium, has identified homozygous carriership of risk-variant rs10191329 in the DYSF-ZNF638 locus to associate with a 3.7 year shorter median time to require a walking aid (EDSS6). Now, we investigate the effect of this allele on pathological outcomes and its associated functional changes. Through this, we aim to validate findings from this GWAS and find putative targets in flanking regions that can ameliorate progressive MS. The MS cohort (n=290) of the Netherlands Brain Bank was genotyped for rs10191329. Associations of the risk allele with clinical and pathological outcomes, including lesion load in the pyramidal tract and cortical lesion rate, were investigated. Using a nested case-control design including all (n=6) homozygous risk carriers (A:A) and n=12 matched homozygous non-risk carriers (C:C), axonal damage (APP), neuronal density, and expression of the flanking genes DYSF and ZNF683 and was assessed using immunohistochemistry, RT-qPCR, and mining of existing microarray and RNAseq data. Now, we biologically validate the findings of the recently discovered MS-severity variant rs10191329 by showing functional changes associated with homozygous carriership of the risk allele. We report a higher amount of lesions, a higher proportion of activated microglia, an higher amount of acute axonal damage, and an increased grey matter neuronal loss. Although the underlying mechanism of these functional changes remains to be unravelled, these findings may open new avenues for countering neurodegeneration in progressing MS.

Aletta van den Bosch
Spatial transcriptomics reveals mechanisms of degeneration and regeneration in multiple sclerosis

In multiple sclerosis (MS), various lesion types are found across the central nervous system, with varying potential for demyelination, remyelination and scar formation. Mixed active/inactive (mixed) lesions with foamy microglia correlate with neuro-axonal damage and more severe clinical and pathological severity, while those with ramified microglia do not. This suggests biological differences between mixed lesions with ramified or foamy microglia. Investigating these differences may elucidate critical mechanisms driving MS lesion progression and repair. We performed high-resolution spatial transcriptomics using the Stereo-seq platform on mixed lesions with ramified microglia, mixed lesions with foamy microglia, and NAWM from the same MS donors (n=8). Unsupervised Seurat clustering and cell-bin pseudo bulk analysis identified distinct gene expression patterns. Gene expression and cell deconvolution of mixed lesions with foamy microglia indicated higher levels of ongoing tissue damage, demyelination, complement activation, iron metabolism, reactive astrocytes, and immunoglobulin production in border and peri-lesion region. In contrast, mixed with ramified microglia showed higher levels of neurite outgrowth and stability of myelin in the border. In conclusion, mixed lesions with ramified microglia may be more prone to remyelination, while those with foamy microglia may be more prone to lesion expansion. This study sheds light on the molecular mechanisms driving MS lesion dynamics and identifies potential targets for therapeutic interventions.