The contribution of DNA methylation to the (dys)function of oligodendroglia in neurodegeneration

Abstract

Neurodegenerative diseases encompass a heterogeneous group of conditions characterised by the progressive degeneration of the structure and function of the central or peripheral nervous systems. The pathogenic mechanisms underlying these diseases are not fully understood. However, a central feature consists of regional aggregation of proteins in the brain, such as the accumulation of β-amyloid plaques in Alzheimer’s disease (AD), inclusions of hyperphosphorylated microtubule-binding tau in AD and other tauopathies, or inclusions containing α-synuclein in Parkinson’s disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Various pathogenic mechanisms are thought to contribute to disease, and an increasing number of studies implicate dysfunction of oligodendrocytes (the myelin producing cells of the central nervous system) and myelin loss. Aberrant DNA methylation, the most widely studied epigenetic modification, has been associated with many neurodegenerative diseases, including AD, PD, DLB and MSA, and recent findings highlight aberrant DNA methylation in oligodendrocyte/myelin-related genes. Here we briefly review the evidence showing that changes to oligodendrocytes and myelin are key in neurodegeneration, and explore the relevance of DNA methylation in oligodendrocyte (dys)function. As DNA methylation is reversible, elucidating its involvement in pathogenic mechanisms of neurodegenerative diseases and in dysfunction of specific cell-types such as oligodendrocytes may bring opportunities for therapeutic interventions for these diseases.

The Role of Hydrogen Sulfide (H2S) in Epigenetic Regulation of Neurodegenerative Diseases: A Systematic Review

“…Emerging research has shed light on the dynamic nature of DNA methylation in neurodegenerative disorders and its impact on disease progression [ 121 ]. For instance, studies have shown altered DNA methylation patterns in genes associated with amyloid-beta processing and tau phosphorylation in Alzheimer’s disease (AD) [ 122 ].…”

“…However, a comprehensive understanding of the specific epigenetic changes and their functional consequences in different neurodegenerative disorders remains an area of active research. Unraveling the complexities of epigenetic regulation in these diseases may lead to identifying biomarkers and novel therapeutic targets, ultimately providing hope for more effective treatments in the future [ 121 , 140 , 141 ].…”

An Epigenetic Manifestation of Alzheimer's Disease: DNA Methylation

“…DNA methylation is an important epigenetic mechanism that mainly occurs at CpG sites and regulates gene transcription by remodeling chromatin conformation [ 55 ]. Extensive research has revealed widespread alterations in DNA methylation patterns in the brain tissues of AD patients [ 56 ]. These differentially methylated genes are involved in AD-related pathological processes, including neurodevelopment, neuroplasticity, inflammatory immune responses, calcium homeostasis, cholesterol metabolism, and myelin metabolism.…”

DNA methylation patterns in the frontal lobe white matter of multiple system atrophy, Parkinson’s disease, and progressive supranuclear palsy: A cross-comparative investigation

“…Additionally, genetic variants in MOBP have been associated with PSP risk [10, 25, 54]. Oligodendrocytes are one of the major cell types in the white matter (up to 75%) that contribute to the formation of myelin sheaths and have been time and again shown to play important roles in several neurodegenerative disease mechanisms [17, 46]. Moreover, DNA methylation patterns suggest accelerated epigenetic ageing in these cells suggesting a vulnerability of oligodendrocytes to ageing [42, 43], which might, at least in part, be contributed by changes in DNA methylation.…”