Dataset Information

Multiple sclerosis severity variant in the DYSF–ZNF638 locus associates with increased neuronal loss and inflammation

ABSTRACT: A recent genome-wide association study identified homozygous carriership of the A allele at variant rs10191329 to associate with faster disability accrual in multiple sclerosis (MS). We investigated the impact of rs10191329AA carriership on MS pathology in the Netherlands Brain Bank MS cohort (n=290) and explored its impact on neuro-axonal damage, lymphocyte accumulation, and protein expression of the flanking genes dysferlin (DYSF) and zinc finger protein 638 (ZNF638) by comparing homozygous carriers (n=6) to non-carriers (rs10191329CC; n=12). Homozygous carriership associated with more amyloid precursor protein (APP)+ bulbs/axons, reflecting increased acute axonal stress, in normal-appearing white matter (NAWM) and white matter lesions, as well as with reduced neuronal density in cortical normal-appearing grey matter (NAGM). Further, homozygous carriers showed a higher proportion of active and mixed active/inactive lesions with foamy microglia, which associate with higher cerebrospinal fluid neurofilament light chain levels. DYSF and ZNF638 were expressed by neurons and oligodendrocytes. In homozygous carriers, NAWM was characterized by a higher proportion of ZNF638+ oligodendrocytes, and NAGM showed more DYSF+ cells. Unexpectedly, nuclear RNA sequencing did not show changes in DYSF or ZNF638 expression in oligodendrocytes and neurons but rather an upregulation of mitochondrial genes in homozygous carriers, specifically those associated with Leber’s hereditary optic neuropathy (LHON), a mitochondrial disease that can have a mechanistic interaction with MS. These data suggest that the association between MS severity and rs10191329 may be driven by increased susceptibility to neurodegeneration, demyelination, and chronic inflammatory lesions. Further understanding of the role of DYSF and ZNF638 as well as LHON-associated mitochondrial pathways in MS pathology may reveal new therapeutic targets to attenuate MS progression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE273954 | GEO | 2025/03/28

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Background. Multiple Sclerosis is a chronic inflammatory disease of the central nervous system (CNS) characterized by autoimmune demyelination and subsequent neuro-axonal degeneration. Despite major progress in deciphering MS immunopathogenesis and treating early stages of disease, CNS-confined processes underpinning later progressive form of MS remain elusive, alluding to the poor accessibility to the target organ. We and others have demonstrated the reliability of profiling DNA methylation, a stable epigenetic marker of genome activity, in neuronal nuclei or bulk tissue to capture relevant molecular changes underlying MS neuropathology. In this study, we examined DNA methylation changes occurring in the normal appearing white matter (NAWM) glial cells of MS patients in comparison to white matter (WM) of non-neurological controls (NNC). Results. We profiled DNA methylation in NeuN-negative nuclei of glial cells, isolated from 38 postmortem NAWM specimens of MS patients (n=8) in comparison to WM of NNC individuals (n=14), using Infinium MethylationEPIC BeadChip. We applied reference-free cell type deconvolution to further reduce cellular heterogeneity and identified 1,226 significant (genome-wide adjusted P-value < 0.05) differentially methylated positions (DMPs) between MS patients and controls. Functional annotation of the affected genes uncovered alterations of processes related to cellular motility, cytoskeleton dynamics, metabolic processes, synaptic support, neuroinflammation as well as signaling pathways, such as Rho, Wnt and TGF-β signaling. A fraction of these changes affected genes which displayed transcriptional differences in the brain of MS patients, as reported by publically available transcriptomic data. Gene ontology analysis of differentially methylated genes according to their constitutive cell type-specific expression in glial cells attributed alteration of cytoskeleton rearrangement and extracellular matrix remodelling to all glial cell types, while some processes, including ion transport, Wnt/TGF-β signaling and immune processes were more specifically linked to oligodendrocytes, astrocytes and microglial cells, respectively. Conclusion. Our findings strongly suggest that NAWM glial cells are highly active, even in the absence of lesional insult, collectively exhibiting a multicellular reaction in response to diffuse inflammation.

Dataset Information

Multiple sclerosis severity variant in the DYSF–ZNF638 locus associates with increased neuronal loss and inflammation

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets