Epigenetic Explorations of Neurological Disorders, the Identification Methods, and Therapeutic Avenues

Abstract

Neurodegenerative disorders are major health concerns globally, especially in aging societies. The exploration of brain epigenomes, which consist of multiple forms of DNA methylation and covalent histone modifications, offers new and unanticipated perspective into the mechanisms of aging and neurodegenerative diseases. Initially, chromatin defects in the brain were thought to be static abnormalities from early development associated with rare genetic syndromes. However, it is now evident that mutations and the dysregulation of the epigenetic machinery extend across a broader spectrum, encompassing adult-onset neurodegenerative diseases. Hence, it is crucial to develop methodologies that can enhance epigenetic research. Several approaches have been created to investigate alterations in epigenetics on a spectrum of scales-ranging from low to high-with a particular focus on detecting DNA methylation and histone modifications. This article explores the burgeoning realm of neuroepigenetics, emphasizing its role in enhancing our mechanistic comprehension of neurodegenerative disorders and elucidating the predominant techniques employed for detecting modifications in the epigenome. Additionally, we ponder the potential influence of these advancements on shaping future therapeutic approaches.

Keywords: Alzheimer’s disease; DNA methylation; Parkinsons’s disease; amyotrophic lateral sclerosis; histone acetylation; neurodegeneration; neuroepigenetics.

Figure 1

APP processing in normal physiological state and disease condition. In the amyloidogenic pathway, APP undergoes processing by β-secretase, leading to the release of sAPPβ and the formation of a membrane-bound fragment, which is then cleaved by γ-secretase, resulting in the production of Aβ and AICD. Conversely, in the non-amyloidogenic pathway, APP is cleaved by α-secretase, yielding sAPPα and a membrane-bound fragment, and subsequent cleavage by γ-secretase results in the generation of p3 and AICD.

Figure 2

Schematic representation of the process leading to neurofibrillar tangle (NFT) formation in Alzheimer’s disease. Under physiological conditions, tau functions as a microtubule-associated protein. Pathological tau, prone to aggregation, undergoes hyper-phosphorylation, resulting in destabilization and dissociation of microtubules. Subsequently, soluble phosphorylated tau molecules aggregate to form NFTs. NFTs, Neurofibrillary tangles.

Figure 3

Illustration depicting the pathway of α-synuclein aggregation. Under pathological conditions, α-synuclein aggregation can occur either in association with the cellular membrane or within the cytosol. When bound to the membrane, monomeric α-synuclein adopts an α-helical conformation; however, ionic dysregulation prompts a conformational shift towards membrane-bound β-sheet structures, leading to self-association and the formation of oligomers and fibrils. The haphazard accumulation of these fibrils contributes to the formation of intracytoplasmic Lewy bodies. Throughout α-synuclein fibrillogenesis, oligomers and amyloid fibrils exert significant toxicity, impairing microtubule dynamics, endoplasmic reticulum–Golgi trafficking, and mitochondrial function.

Figure 4

Function of TDP-43 in Normal and Disease Conditions. TDP-43 plays diverse functional roles including initiation of transcription, pre-mRNA splicing, miRNA processing, mRNA transport, and mRNA stability. However, under pathological conditions, TDP-43 is depleted from the nucleus and aggregates in the cytoplasm in hyperphosphorylated, ubiquitinated, and cleaved forms (CTFs), which are characteristic features of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) proteinopathies.

Figure 5

A general outline of epigenetic modification in neurodegeneration. Histone acetylation mediated by HAT is associated with gene expression, while histone methylation is mediated by HMT; monomethylation of histone is associated with gene expression whereas trimethylation causes gene repression. DNA methylation is mediated by DNA methyltransferase (DNMT) which is also related with gene repression. Abbreviation: Me—methylation; Ac—acetylation, Histone acetyltransferase (HAT), histone methyltransferase (HMT). The red crosses show inhibition of gene expression.

Figure 6

Visualization of diverse methodologies utilized in the analysis of DNA methylation, covering CpG and non-CpG regions. Method selection considerations include assessing the desired resolution, specificity, and coverage for a thorough examination of DNA methylation patterns, especially within both known and unknown genomic contexts. Abbreviation: me—methylated, unme—unmethylated.

Figure 7

Methods for analyzing histone modification, including Chromatin Immunoprecipitation (ChIP), ChIP-sequencing (ChIP-seq), Enzyme-Linked Immunosorbent Assay (ELISA), Mass Spectrometry (MS), and Proximity Ligation Assay (PLA). Consideration for method selection depends on the desired scale, specificity, and quantitative precision of histone modification analysis.