Epigenetic mechanisms in neurological and neurodegenerative diseases

Abstract

The role of epigenetic mechanisms in the function and homeostasis of the central nervous system (CNS) and its regulation in diseases is one of the most interesting processes of contemporary neuroscience. In the last decade, a growing body of literature suggests that long-term changes in gene transcription associated with CNS's regulation and neurological disorders are mediated via modulation of chromatin structure. "Epigenetics", introduced for the first time by Waddington in the early 1940s, has been traditionally referred to a variety of mechanisms that allow heritable changes in gene expression even in the absence of DNA mutation. However, new definitions acknowledge that many of these mechanisms used to perpetuate epigenetic traits in dividing cells are used by neurons to control a variety of functions dependent on gene expression. Indeed, in the recent years these mechanisms have shown their importance in the maintenance of a healthy CNS. Moreover, environmental inputs that have shown effects in CNS diseases, such as nutrition, that can modulate the concentration of a variety of metabolites such as acetyl-coenzyme A (acetyl-coA), nicotinamide adenine dinucleotide (NAD(+)) and beta hydroxybutyrate (β-HB), regulates some of these epigenetic modifications, linking in a precise way environment with gene expression. This manuscript will portray what is currently understood about the role of epigenetic mechanisms in the function and homeostasis of the CNS and their participation in a variety of neurological disorders. We will discuss how the machinery that controls these modifications plays an important role in processes involved in neurological disorders such as neurogenesis and cell growth. Moreover, we will discuss how environmental inputs modulate these modifications producing metabolic and physiological alterations that could exert beneficial effects on neurological diseases. Finally, we will highlight possible future directions in the field of epigenetics and neurological disorders.

Keywords: DNA methylation; Parkinson disease; epigenetics; epilepsy; neurodegeneration; postranslational modification.

Figure 1

Linking lifestyle with genome expression. DNA and the proteins that provides chromatin structure are targets of multiple modifications. In this way, changes in our lifestyle (diets or physical activity) via the modulation of the metabolism alters the concentration ratio of different metabolites. The availability and cellular compartamentalization of these metabolites alters the activity of proteins capable to elicit epigenetic modifications, contributing to the specificity of the genome expression. NAD, nicotine adenine dinucleotide (Modified from Sassone-Corsi, 2013).

Figure 2

Histone posttranslational modifications. (A) Schemes representing the interaction of the N-terminal dominium of acetylated histones with the DNA strand (A) and the interaction of a non-acetylated histone with the DNA strand (B). It can be noticed that acetylated histones have a minor interaction with DNA strand compared with that of non-acetylated histones whose positive charges are attracted to negative charges of DNA. (C) On the other hand different specific marks of methylation of histone 3 are associated with both transcriptional activation (C) and repression (D). Also a specific mark of phosphorylation on the (S10) amino acid of histone 3 has been associated with transcriptional activation (E) so the lack of this mark may be associated with transcriptional repression (F).

Figure 3

DNA methylation. Scheme showing the addition of a methyl group on the 5 carbon of cytosine in the context of 5′-CpG-3′ dinucleotide (A). The maintenance of DNA methylation is accomplished by DNA methyl-transferases (DNMT1) when DNA replication occurs (B).

Figure 4

REST structure and their interactions with other proteins. REST modulates the expression of its target genes by recruiting a host of lysine-modifying enzymes. Numbers refer to amino acid residues. Colored molecules possess enzymatic activity.