sPD: sporadic Parkinson’s disease; PBMC: peripheral blood mononuclear cell; CSF: cerebrospinal fluid; DA: dopaminergic; SN: Substantia nigra; controls: general population without PD.
2. Current Insights
The expression of genes involved in familial forms of PD seems to also be dysregulated in sporadic PD patients. However, it remains unclear whether the change in gene expression corresponds to a pathophysiological mechanism, a marker of degeneration or a protective effect.
For
SNCA, its overexpression seems to be a prerequisite for aSyn aggregation leading to Lewy body (LB) formation
[42]. Hypomethylation of
SNCA could be involved in its overexpression. A pathophysiological mechanism suggested is the sequestration of cytoplasmic DNMT1 by the aggregates leading to the dysregulation of aSyn homeostasis
[43]. The decrease in the brain level of miR-34b/c could also participate in the overexpression of
SNCA [44].
The increase in LRRK2 kinase activity mediated by the G2019S and other disease-causing mutations raises the question whether LRRK2 is overexpressed in sporadic PD
[45]. Increased expression of LRRK2 was found in the brains of PD patients, without increased transcripts
[23]. A step in the pathophysiology could be a decrease in miR-205 expression, but the causes of this dysregulation is not clear
[23]. Furthermore, the regulation of LRRK2 expression by immune stimulation in blood tissue suggests the implication of neuro-inflammatory mechanisms
[46] and could represent an accessible epigenetic biomarker.
Due to alternative splicing and multiple splice isoforms, it is more challenging to understand the relationship between Parkin expression and its pathophysiology in sporadic PD
[47]. Epigenetic mechanisms could be involved in the modification of the PRKN expression profile.
Mitochondrial damage could induce overexpression of PINK1
[48]. However, the role of increased PINK1 expression is unclear. It could be either protective or participating in neuronal death. Inflammation in PD seems to be most intense at the beginning, just after clinical diagnosis, attenuating in later stages
[49][50]. It has been reported that miR-27a is downregulated in macrophages after stimulation
[51]. The decrease in miR-27a observed in early PD may be involved in the inflammation-induced upregulation of PINK1.
Decreased transcription and translation of DJ-1 in sporadic forms of PD may also be involved in the pathophysiology of the disease
[37]. Oxidative stress leads to the expression of miR-494-3p
[52]. The induction of miR-4639-5p expression by oxidative stress remains to be explored. The researchers can hypothesize that miRs could be sensors of oxidative stress and contribute to the cellular response by downregulating DJ1.
Decreased GCase protein levels and activity may also be involved in the development of sporadic PD
[40].
MiRNA and lncRNA mechanisms may be involved in the regulation of GBA expression but their change in expression level in sporadic PD patients is not clear. The mechanisms regulating miRNA expression are not well elucidated. An interesting approach would be to explore DNA methylation patterns or histone modifications at the transcription sites of these miRNA-regulating genes involved in monogenic forms of PD. Furthermore, epigenetic modifications involve tissue-specific processes. The observation of these mechanisms in pathologically relevant cell types and access to these cells is complex.
Analysis of native brain tissue allows the researchers to observe epigenetic changes that take place in the brains of PD subjects. However, these analyses are limited to the post-mortem brain and longitudinal studies cannot be performed to assess the dynamics of epigenetic mechanisms. The collection of more accessible peripheral tissues such as blood or CSF allows an analysis in living individuals over time. However, since the methylation profile is tissue-specific, observations in these tissues do not confirm identical modifications in neurons. Since LRRK2 expression seems to play a role in the inflammatory response, the study of the regulation of its expression in the blood immune cells of PD patients could be interesting. The use of animal models of PD for the analysis of epigenetic alterations presents some difficulties since epigenetic mechanisms are species-specific, and these models may not be representative of epigenetic alterations in humans. However, they can allow for the study of specific neuronal populations
[53].
Human iPSC-derived neurons have been developed, which allows for the generation of specific neuron lineages such as dopaminergic neurons derived from PD patients
[54][55]. However, the generation of these cells requires cellular reprogramming based on epigenetic modifications resulting in “epigenetic rejuvenation”
[56] and may bias the study of epigenetic alterations associated with age in PD. More recent direct conversion techniques make it possible to obtain induced neurons (iNs) with the same epigenetic age as their original fibroblasts. This conversion leaves the most age-related epigenetic marks intact but nevertheless leads to a reorganization of large parts of the epigenome
[57]. On the other hand, significant epigenetic changes are largely cell type specific and the value of maintaining epigenetic marks in adult fibroblasts is controversial.
Although these in vitro models have limitations, they offer the opportunity to directly study putative effects of epigenetic modifications on gene expression. Moreover, they allow the development of 3D brain organoids or spheroids (cerebral organoids) with a better reproduction of the cerebral environment. This enables for better understanding of the epigenetic modifications that take place in neurons and other cell lineages such as astrocytes and microglia, also suspected in the pathophysiology of PD
[55]. In addition to providing an understanding of the pathophysiology, epigenetic modifications could also allow for the development of biomarkers for the diagnosis, prognosis and monitoring of PD
[58]. The demonstration of the causality of epigenetic mechanisms in the onset or progression of the disease could allow for the emergence of new therapeutic targets.
Epigenomic identity may also be mediated by chromosome folding
[59]. Recent studies reveal that the 3D organization of the genome correlates with epigenetic modifications and that these modifications predict the structure of chromatin
[59][60]. Moreover, changes in the 3D architecture of chromosomes have been observed in cancer cells
[61]. This new field of analysis could allow a better understanding of the involvement of epigenetic modifications in PD.