The Role of Epigenetics in Neuroinflammatory-Driven Diseases

Abstract

Neurodegenerative disorders are characterized by the progressive loss of central and/or peripheral nervous system neurons. Within this context, neuroinflammation comes up as one of the main factors linked to neurodegeneration progression. In fact, neuroinflammation has been recognized as an outstanding factor for Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and multiple sclerosis (MS). Interestingly, neuroinflammatory diseases are characterized by dramatic changes in the epigenetic profile, which might provide novel prognostic and therapeutic factors towards neuroinflammatory treatment. Deep changes in DNA and histone methylation, along with histone acetylation and altered non-coding RNA expression, have been reported at the onset of inflammatory diseases. The aim of this work is to review the current knowledge on this field.

Keywords: Alzheimer’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; chronic neuroinflammation; epigenetics; multiple sclerosis; neurodegeneration.

Figure 1

Schematic representation of epigenetic mechanisms affecting histones and DNA nucleobases resulting in modified DNA methylation status and genomic instability.

Figure 2

Accumulation of abnormal neurotic plaques and neurofibrillary tangles are the main pathological traits of AD. The first is related to the incorrect sequential cleavage of the amyloid precursor generating the fibrous protein enriched of β-sheet secondary structures. The second is the result of hyperphosphorylation of microtubule-associated tau protein in neurons leading to cytoskeletal changes. Among epigenetic changes, the acetylation processes lead to several effects. The reduction of Sirt1, a class III HDAC, determines a lack of histone deacetylation with downstream effects resulting in the development of Aβ plaques. However, inflammatory processes triggered by reactive microglia in plaques orchestrates tau hyperphosphorylation, where H3K9 acetylation by HDAC6 activity has been found to be implicated in the epigenic changes. Moreover, aberrant DNA methylation, especially DNMTs and TET, are associated to mitochondrial dysfunction causing the homeostatic loss of ROS balance which in turn is responsible for the apoptotic death of neurons. Finally, epigenetic changes also drive the formation of apolipoprotein E isoforms that show increased production and reduced degradation capacity of Aβ plaques; miR-9 is one the main miRNAs involved in AD pathogenesis, since its reduction determines a decrease of BACE1 and the activation of CAMKK2 which are responsible for Aβ plaques and p-tau, respectively. On the other hand, its upregulation control SIRT1 activity proves the correlation between miRNA and chromatin remodeling in AD pathological traits; MAPK/ERK activation is related to miR-125b for p-tau formation, whereas miR-146 expression is strictly linked to NF-κB. Other miRNAs, such as miR-132/-212 and the interaction between miR-29 and miR-107, directly correlate with Aβ plaques and p-tau accumulation.

Figure 3

Epigenetics in PD. DNA hypomethylation of SNCA is associated with increase of SNCA expression. DNMT1 (a regulator of DNA methylation) plays an important role in SNCA expression. DNMT1 is mainly located in the nucleus of neurons, and α-Syn aggregation leads to cytoplasmic sequestration of DNMT1, resulting in decreased nuclear localization of DNMT1, which is likely to be involved in the pathogenesis of PD.

Figure 4

Mutations in several genes that have been implicated in the pathophysiology of amyotrophic lateral sclerosis (ALS) have been reported as triggers for disease neuroinflammation and neurodegeneration. TDP-43 inclusions, SOD1, C9orf72, TARDBP, and FUS gene mutations have been identified as further causative or highly associated with ALS pathogenesis. Moreover, differentially methylated positions (DMPs) and differentially methylated regions (DMRs) of specific genes have been suggested as ALS contributors. Other mechanisms are largely correlated with ALS: for instance, microglia-mediated inflammatory response can directly contribute to motor neuron dysfunction and death, producing inflammatory mediators and reactive oxygen and nitrogen species.

Figure 5

Schematic representation of epigenetic modifications in B cells at the clinical onset of MS. ATXN1 gene is hypomethylated in four sites by TET1, of which mRNA is upregulated. PUM1, with miR-19 and miR-130, stabilizes ATXN1 mRNA, leading to the increase in ATXN1 protein levels.