Does the Expression and Epigenetics of Genes Involved in Monogenic Forms of Parkinson's Disease Influence Sporadic Forms?

Abstract

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. This review will focus on the epigenetic mechanisms regulating their expression, since these are the genes for which we currently have the most information available. Despite technical challenges, epigenetic epidemiology offers new insights on revealing altered biological pathways and identifying predictive biomarkers for the onset and progression of PD.

Keywords: DNA methylation; Parkinson’s and related diseases; Parkinson’s disease; RNA-based gene regulation; epigenetic; genetic; histone modification; neurodegeneration.

Figure 1

Epigenetic mechanisms and dysregulation of α synuclein. Abbreviations: 5′UTR: 5′ untranslated region; 3′UTR: 3′ untranslated region; 1–6: exon 1 to 6; CGI: CpG island; AAA: polyadenylation; DNMT1: DNA methyltransferase 1; mRNA: messenger RNA; miRNA: microRNA; TSS: transcription start site.

Figure 2

Distribution of histone modifications in the SNCA gene. Abbreviations: 5′UTR: 5′ untranslated region; 3′UTR: 3′ untranslated region; 1–6: exon 1 to 6; TSS: transcription start site. Histone modifications, H3K4me3 (green), H3K27ac (blue) and H3K27me3 (red), in the SNCA gene from Substantia nigra tissues of two healthy adult postmortem brain samples. Adapted from Roadmap Epigenomics Database.

Figure 3

Current known variants in LRRK2 illustrated at the protein level (image obtained from MDS genes). The protein kinase domain of the LRRK2 protein where the G2019S mutation is located is visible in pink in the figure.

Figure 4

Scheme of mitophagy induced by PINK1 and Parkin. Abbreviation: u: ubiquitin. Under stress factors, PINK1 accumulates and recruits Parkin to the outer membrane of mitochondria. PINK1 and Parkin signaling allows autophagosome formation. Fusion of the autophagosome with the lysosome leads to mitophagy.