Multiple sclerosis severity variant in DYSF-ZNF638 locus associates with neuronal loss and inflammation

The genetic variant rs10191329^AA has been identified to associate with faster disability accrual in multiple sclerosis (MS). We investigated the impact of rs10191329^AA carriership on MS pathology and flanking genes dysferlin (<i>DYSF</i>) and zinc finger protein 638 (<i>ZNF638</i>) in the Netherlands Brain Bank cohort (<i>n</i> = 290) by comparing rs10191329^AA (<i>n</i> = 6) to matched rs10191329^CC carriers (<i>n</i> = 12). rs10191329^AA carriership associated with more acute axonal stress, reduced layer 2 neuronal density, and a higher proportion of lesions with foamy microglia. In rs10191329^AA donors, normal appearing white matter was characterized by a higher proportion of ZNF638⁺ oligodendrocytes, and normal appearing gray matter showed more DYSF⁺ cells. Nuclear RNA sequencing showed an upregulation of mitochondrial genes in rs10191329^AA carriers. These data suggest that MS severity associates with an increased susceptibility to neurodegeneration and chronic inflammation. Understanding the role of DYSF, ZNF638, and mitochondrial pathways may reveal new therapeutic targets to attenuate MS progression.