Epigenetic Regulation in Neurodegenerative Diseases

Abstract

Mechanisms of epigenetic regulation, including DNA methylation, chromatin remodeling, and histone post-translational modifications, are involved in multiple aspects of neuronal function and development. Recent discoveries have shed light on critical functions of chromatin in the aging brain, with an emerging realization that the maintenance of a healthy brain relies heavily on epigenetic mechanisms. Here, we present recent advances, with a focus on histone modifications and the implications for several neurodegenerative diseases including Alzheimer's disease (AD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). We highlight common and unique epigenetic mechanisms among these situations and point to emerging therapeutic approaches.

Keywords: Alzheimer’s disease; Huntington’s disease; chromatin; epigenetics; histone modifications; neurodegenerative diseases.

Figure 1.

Chromatin Alterations in Brain Aging and Disease. We summarize global changes to histone modifications and related alterations that occur in aging, AD, and HD. We note that due to the complexity of the genome, with both losses and gains usually reported for histone marks in these conditions, this schematic represents a simplified model of more intricate changes. From the studies highlighted here, a general theme emerges in which aging and HD are primarily characterized by reduced levels of modifications usually associated with open chromatin (in aging, H3K36me3 and H3K27ac [17]; in HD, H3K4me3, H3K9ac, H3K14ac, and H3K12ac [, 91]) and increases in marks associated with closed chromatin (in aging, H3K9me and H3K27me3 [17]; in HD, H3K9me3 [43, 45]). In Drosophila heads however, reduced levels of H3K9me3 and HP1 with age are associated with increased expression of genes that are normally silenced [18]. In AD, the alterations appear to be distinct with global losses of heterochromatin marks (H3K9me2 in Drosophila τ model [36]), as well as locus-specific losses and gains of activating marks (H3K4me3 and H3K27ac in a mouse model [27], and H4K16ac in the human AD brain [33]). Changes to the nuclear architecture, for example loss of the lamin cytoskeleton in tauopathies, may also contribute to reduced levels of heterochromatic marks and gene expression imbalances. In HD, the pathological accumulations of nuclear and cytoplasmic inclusion bodies interact with several chromatin factors including CBP and HDAC4, providing a direct mechanism by which these pathologies promote alterations to chromatin structure. Abbreviations: AD, Alzheimer’s disease; CBP, CREB-binding protein HD, Huntington’s disease; HDAC, histone deacetylase; NFTs, neurofibrillary tangles; REST, Repressor element 1-silencing transcription factor.