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Review
. 2021 Dec;47(7):897-909.
doi: 10.1111/nan.12757. Epub 2021 Aug 5.

Neurodegenerative movement disorders: An epigenetics perspective and promise for the future

Megha Murthy  1   2 , Yun Yung Cheng  1 , Janice L Holton  1   2 , Conceição Bettencourt  1   3
Affiliations
Review

Neurodegenerative movement disorders: An epigenetics perspective and promise for the future

Megha Murthy et al. Neuropathol Appl Neurobiol. 2021 Dec.

Abstract

Neurodegenerative movement disorders (NMDs) are age-dependent disorders that are characterised by the degeneration and loss of neurons, typically accompanied by pathological accumulation of different protein aggregates in the brain, which lead to motor symptoms. NMDs include Parkinson's disease, multiple system atrophy, progressive supranuclear palsy, and Huntington's disease, among others. Epigenetic modifications are responsible for functional gene regulation during development, adult life and ageing and have progressively been implicated in complex diseases such as cancer and more recently in neurodegenerative diseases, such as NMDs. DNA methylation is by far the most widely studied epigenetic modification and consists of the reversible addition of a methyl group to the DNA without changing the DNA sequence. Although this research field is still in its infancy in relation to NMDs, an increasing number of studies point towards a role for DNA methylation in disease processes. This review addresses recent advances in epigenetic and epigenomic research in NMDs, with a focus on human brain DNA methylation studies. We discuss the current understanding of the DNA methylation changes underlying these disorders, the potential for use of these DNA modifications in peripheral tissues as biomarkers in early disease detection, classification and progression as well as a promising role in future disease management and therapy.

Keywords: DNA methylation; EWAS; brain tissue; epigenetics; epigenomics; movement disorders; neurodegeneration; pathogenesis.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

FIGURE 1
FIGURE 1
Schematic representation of the complex landscape of epigenetic mechanisms. DNA can often be modified at cytosine residues by the addition of chemical groups. Cytosines can be modified by methylation, hydroxymethylation (hmC), formylation (fC) and carboxylation (caC). Nucleosomes, which are the basic structural unit of chromatin and are composed of DNA wrapped around histone proteins, can change position to increase or decrease DNA accessibility. This DNA accessibility can be modified by the incorporation of histone variants and the addition of post‐translational modifications to histones, such as methylation, acetylation, phosphorylation and ubiquitination. Non‐coding RNAs, including microRNAs (miRNAs) and long non‐coding RNAs (lncRNAs), also play an important role in transcription regulation and in a broader definition are considered another epigenetic mechanism. While miRNAs are involved in directing RNAs for degradation, lncRNAs are associated with other complexes and can activate or repress transcription. This figure was created with BioRender.com
FIGURE 2
FIGURE 2
Schematic representation of the dynamic cycle for DNA cytosine modifications. Unmethylated cytosine (5C) can be converted into 5‐methylcytosine (5mC) through DNA methyltransferases (DNMTs). Active demethylation of 5mC, 5‐hydroxymethylcytosine (5hmC), 5‐formylcytosine (5fC) and 5‐carboxylcytosine (5caC) occurs via oxidation by ten‐eleven translocation (TET) enzymes and decarboxylation (?)/thymine DNA glycosylase (TDG)‐dependent base excision repair (BER)
FIGURE 3
FIGURE 3
A timeline summarising the progress of studies investigating DNA modifications in brain tissue of neurodegenerative movement disorders (NMDs). Different colours represent different NMDs and different shapes represent different methodological approaches and study designs, as depicted in the figure caption. DLB, dementia with Lewy bodies; EWAS, epigenome‐wide association study; FRDA, Friedreich's ataxia; HD, Huntington's disease; MSA, multiple system atrophy; PD, Parkinson's disease; PSP, progressive supranuclear palsy; 5mC, 5‐methylcytosine; 5hmC, 5‐hydroxymethylcytosine
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