DNA Methylation Signature of Aging: Potential Impact on the Pathogenesis of Parkinson’s Disease

Abstract

Regulation of gene expression by epigenetic modifications means lasting and heritable changes in the function of genes without alterations in the DNA sequence. Of all epigenetic mechanisms identified thus far, DNA methylation has been of particular interest in both aging and age-related disease research over the last decade given the consistency of site-specific DNA methylation changes during aging that can predict future health and lifespan. An increasing line of evidence has implied the dynamic nature of DNA (de)methylation events that occur throughout the lifespan has a role in the pathophysiology of aging and age-associated neurodegenerative conditions, including Parkinson’s disease (PD). In this regard, PD methylome shows, to some extent, similar genome-wide changes observed in the methylome of healthy individuals of matching age. In this review, we start by providing a brief overview of studies outlining global patterns of DNA methylation, then its mechanisms and regulation, within the context of aging and PD. Considering diverging lines of evidence from different experimental and animal models of neurodegeneration and how they combine to shape our current understanding of tissue-specific changes in DNA methylome in health and disease, we report a high-level comparison of the genomic methylation landscapes of brain, with an emphasis on dopaminergic neurons in PD and in natural aging. We believe this will be particularly useful for systematically dissecting overlapping genome-wide alterations in DNA methylation during PD and healthy aging, and for improving our knowledge of PD-specific changes in methylation patterns independent of aging process.

DNA Methylation Analysis in Monozygotic Twins Discordant for ALS in Blood Cells

“…It is critical to note that the effect of the age-associated intra-pair difference in DNA methylation status must not be disregarded in such studies though the biological factors specific to individual pairs are matched out in MZ twins. 52 Empirical evidence confirming this effect came from the observation that twin correlation on genome-wide DNA methylation declines with age (Supplemental Figure 2). If this increasing divergence of the epigenome with age actually roots from stochastic alterations, then co-twins in identical twin pairs should be affected differently along the natural course of epigenetic drift, leading to diminishing within-pair twin correlations on global DNA methylation.…”