Epigenetic mechanisms during ageing and neurogenesis as novel therapeutic avenues in human brain disorders

Abstract

Ageing is the main risk factor for human neurological disorders. Among the diverse molecular pathways that govern ageing, epigenetics can guide age-associated decline in part by regulating gene expression and also through the modulation of genomic instability and high-order chromatin architecture. Epigenetic mechanisms are involved in the regulation of neural differentiation as well as in functional processes related to memory consolidation, learning or cognition during healthy lifespan. On the other side of the coin, many neurodegenerative diseases are associated with epigenetic dysregulation. The reversible nature of epigenetic factors and, especially, their role as mediators between the genome and the environment make them exciting candidates as therapeutic targets. Rather than providing a broad description of the pathways epigenetically deregulated in human neurological disorders, in this review, we have focused on the potential use of epigenetic enzymes as druggable targets to ameliorate neural decline during normal ageing and especially in neurological disorders. We will firstly discuss recent progress that supports a key role of epigenetic regulation during healthy ageing with an emphasis on the role of epigenetic regulation in adult neurogenesis. Then, we will focus on epigenetic alterations associated with ageing-related human disorders of the central nervous system. We will discuss examples in the context of psychiatric disorders, including schizophrenia and posttraumatic stress disorders, and also dementia or Alzheimer’s disease as the most frequent neurodegenerative disease. Finally, methodological limitations and future perspectives are discussed.

Network modules linking expression and methylation in prefrontal cortex of schizophrenia

“…The influence of DNA methylation in gene transcription can be stable and heritable across cell generations, and also reversible according to external condition changes [23]. The dynamics of DNA methylation plays a vital role in the pathogenesis of SCZ, especially in neuronal diversity, plasticity and neurogenesis [24, 25]. Besides environmental and developmental effects, DNA methylation can also be influenced by sequence variants (e.g., genotype variation or specific allele on a locus), which represents a methylation QTL (meQTL).…”

Non-genetic Transgenerational Inheritance of Acquired Traits in Drosophila

“…Many behavioral traits, including cognitive functions, may be transgenerationally affected by experiences and environmental factors in mammals, most likely through epigenetic mechanisms [92]. Memory is an essential cognitive function which declines during aging and is impaired in most neurodegenerative diseases such as Alzheimer's disease; it is subjected to various epigenetic regulations, providing novel therapeutic avenues to combat cognitive disorders [12,93]. Therefore, studying TEI of memory is of immense importance to our understanding of mental health and diseases.…”

The influence of aging on the methylation status of brain‐derived neurotrophic factor gene in blood

“…In this context, it is plausible that the aging‐associated changes in gene expression may be because of alteration in DNA methylation (DNAm) in the brain. In fact, several studies have demonstrated age‐associated DNAm, such as hypermethylation or hypomethylation, in the brain . With regard to BDNF, Keleshian and associates reported that the methylation rate at promoter I of the BDNF gene in the frontal cortex was positively correlated with aging.…”

“…In fact, several studies have demonstrated age-associated DNAm, such as hypermethylation or hypomethylation, in the brain. [10][11][12][13][14] With regard to BDNF, Keleshian and associates 15 reported that the methylation rate at promoter I of the BDNF gene in the frontal cortex was positively correlated with aging. McKinney and colleagues 16 also demonstrated that methylation levels at the promoters of the BDNF gene in the orbital frontal cortex in an elderly cohort were higher than those in a younger cohort.…”