Parkinson’s disease (PD) is a disorder characterized by a triad of motor symptoms (akinesia, rigidity, resting tremor) related to loss of dopaminergic neurons mainly in the Substantia nigra pars compacta. Diagnosis is often made after a substantial loss of neurons has already occurred, and while dopamine replacement therapies improve symptoms, they do not modify the course of the disease. Although some biological mechanisms involved in the disease have been identified, such as oxidative stress and accumulation of misfolded proteins, they do not explain entirely PD pathophysiology, and a need for a better understanding remains. Neurodegenerative diseases, including PD, appear to be the result of complex interactions between genetic and environmental factors. The latter can alter gene expression by causing epigenetic changes, such as DNA methylation, post-translational modification of histones and non-coding RNAs. Regulation of genes responsible for monogenic forms of PD may be involved in sporadic PD.
1. Introduction
Parkinson’s disease (PD) is a neurodegenerative disease, characterized by progressive degeneration of the dopaminergic neurons of the
Substantia nigra pars compacta. Its pathology is multifactorial; influenced by both environmental and genetic determinants [
1]. Several pathogenic mutations have been linked to autosomal dominant or recessive forms of PD. The discovery of these genes allowed a new insight into the pathophysiology of this disorder [
2]. Pathological hallmarks of PD include the presence of cytoplasmic inclusions, called Lewy bodies (LB), mainly composed of aggregated αsynuclein (α-Syn) [
3]. Multiplication and point mutations of
SNCA encoding α-Syn are now recognized to cause autosomal dominant PD and they are suspected of promoting α-Syn aggregation. The
PINK1,
PARKIN and
DJ1 genes encode for proteins required by mitochondria, which are essential components of neurons for ATP synthesis, calcium storage, lipid metabolism and neuronal survival [
2,
4]. The fact that mutations in these genes lead to PD is a strong argument that mitochondrial dysfunction is involved in the pathophysiology of PD.
Genetic mutations account for only 10% of patients with PD, and therefore environmental exposure seems to play a major role in PD [
2]. Epigenetic modulation of gene expression by environmental factors is increasingly studied. Epigenetic regulation involves different mechanisms such as modification of the histones of chromatin and DNA methylation changes [
5]. Chromatin is a dynamic scaffold and modification of its main components, the histones, can modulate gene expression [
6]. The effect of histone modification is mediated either by directly affecting the structure of chromatin, by disrupting the binding of proteins that associate with chromatin or by attracting certain effector proteins to chromatin [
5]. Histone acetylation decreases the compression of chromatin and promotes gene transcription. Methylation of histone H3 lysine 4 (H3K4), H3K36 and H3K79 are marks of transcriptional activation, whereas methylation of H3K9, H3K27 and H4K20 are repressive modifications of transcription, involving the recruitment of methylating enzymes and HP1 to the gene promoter [
7].
Direct DNA methylation is also a key epigenetic mechanism regulating gene expression. It is a reversible modification of DNA, which consists of the addition of a methyl group to the fifth carbon position of a cytosine, converting it to 5-methylcytosine (5mC). The transfer of a methyl group is carried out by DNA methyltransferase (DNMT) enzymes [
8]. This epigenetic mark is frequently found within a 5’-Cytosine-phosphate-Guanosine sequence, called a CpG site [
9]. DNA methylation is not homogeneously distributed in the genome, CpG sites are clustered in sequences called CpG islands (CGI). Methylation of promoter-associated CGIs can impair transcription factor binding or recruit repressive binding proteins, thus reduce gene expression [
10]. Cytosine methylation is mediated by DNMTs, which can be classified as de novo (DNMT3A and DNMT3B) and maintenance (DNMT1) [
11].
Epigenetic regulation is also closely linked to non-coding RNAs. Non-coding RNAs are classified according to their size, with small RNAs less than 200 nucleotides long and long non coding (LncRNAs) longer than 200 nucleotides [
12]. Among the small non-coding RNAs, microRNAs (miRNAs) are the most studied. Mature miRNAs bind to complementary sequences of the target messenger RNA (mRNA), often in the 3′ untranslated region (3’UTR), and can increase mRNA degradation but also inhibit translation without reducing mRNA expression [
13,
14]. The regulation of gene expression by Long non-coding RNAs (LncRNAs) is not yet fully understood. However, they appear to be important genomic regulators, from the epigenetic to the post-translational level [
15].
Epigenetic mechanisms influencing the development of sporadic PD have yet to be identified. Genes involved in monogenic forms of PD could be over- or under-expressed in the sporadic form compared to the general population without PD (controls). In the context of altered expression of these genes in sporadic forms, it can be assumed that epigenetic mechanisms may be involved in this dysregulation (Table 1).
Table 1. Expression profile and epigenetic changes observed for genes involved in monogenic forms of PD.
Studies |
Tissues Analyzed |
Proteins in Controls vs. sPD |
mRNA in Controls vs. sPD |
DNA Methylation in Controls vs. sPD |
MiRNA Expression in Controls vs. sPD |
Reference |
SNCA |
Grundemann et al., 2008 |
Brain: DA neurons of SN |
Increase |
Increase |
- |
- |
[16] |
Jowaed et al., 2010/Matsumoto et al., 2010 |
Brain |
- |
- |
Hypomethylation |
- |
[17,18] |
Pihlstrom et al., 2015/Ai et al., 2014/Tan et al., 2014 |
Blood immune cells |
- |
- |
Hypomethylation |
- |
[19,20,21] |
Minones-Moyano et al., 2011 |
Brain |
- |
- |
- |
Decrease miR-34b/c |
[22] |
LRRK2 |
Cho et al., 2013 |
Brain: frontal cortex/striatum |
Increase |
No difference |
- |
Decrease miR-205 |
[23] |
Cook et al., 2017 |
Blood |
Increase |
- |
- |
- |
[24] |
Tan et al., 2014 |
Blood immune cells |
- |
- |
Hypomethylation |
- |
[21] |
PRKN |
Beyer et al., 2008 |
Brain |
- |
Increase in variant TV3 and TV12 |
- |
- |
[25] |
Cai et al., 2011 |
Blood immune cells |
- |
- |
No difference |
- |
[26] |
De Mena et al., 2013 |
Brain |
- |
- |
No difference |
- |
[27] |
Eryilmaz et al., 2017 |
Blood immune cells |
- |
- |
Hypomethylation |
- |
[28] |
Ding et al., 2016 |
Plasma |
- |
- |
- |
Decrease miR-181a |
[29] |
Xing et al., 2020 |
Brain |
- |
- |
- |
Decrease miR-218 |
[30] |
Serafin et al., 2015 |
Plasma |
- |
- |
- |
Increase miR-103a-3p |
[31] |
PINK1 |
Muqit et al., 2006 |
Brain |
Increase ∆1-PINK1 |
- |
- |
- |
[32] |
Blackinton et al., 2007 |
Brain: SN |
- |
No difference |
- |
- |
[33] |
Navarro-Sanchez et al., 2018 |
Brain: SN |
- |
- |
No difference |
- |
[34] |
Fazeli et al., 2020/Dos Santos et al., 2018 |
PBMC/CSF |
- |
- |
- |
Decrease miR-27a |
[35,36] |
DJ1 |
Kumaran et al., 2009 |
Brain |
Decrease |
Decrease |
- |
- |
[37] |
Tan et al., 2016 |
Blood immune cells |
- |
- |
No difference |
- |
[38] |
Chen et al., 2017 |
Plasma |
- |
- |
- |
Increase miR-4639-5p |
[39] |
GBA |
Murphy et al., 2014 |
Brain |
Decrease |
No difference |
- |
- |
[40] |
Moors et al., 2019 |
Brain |
- |
No difference |
- |
- |
[41] |
Eryilmaz et al., 2017 |
Blood immune cells |
- |
- |
No difference |
- |
[28] |
This entry is adapted from the peer-reviewed paper 10.3390/genes13030479