Epigenetic regulation in Parkinson's disease

Abstract

Recent efforts have shed new light on the epigenetic mechanisms driving gene expression alterations associated with Parkinson's disease (PD) pathogenesis. Changes in gene expression are a well-established cause of PD, and epigenetic mechanisms likely play a pivotal role in regulation. Studies in families with PD harboring duplications and triplications of the SNCA gene have demonstrated that gene dosage is associated with increased expression of both SNCA mRNA and protein, and correlates with a fulminant disease course. Furthermore, it is postulated that even subtle changes in SNCA expression caused by common variation is associated with disease risk. Of note, genome-wide association studies have identified over 30 loci associated with PD with most signals located in non-coding regions of the genome, thus likely influencing transcript expression levels. In health, epigenetic mechanisms tightly regulate gene expression, turning genes on and off to balance homeostasis and this, in part, explains why two cells with the same DNA sequence will have different RNA expression profiles. Understanding this phenomenon will be crucial to our interpretation of the selective vulnerability observed in neurodegeneration and specifically dopaminergic neurons in the PD brain. In this review, we discuss epigenetic mechanisms, such as DNA methylation and histone modifications, involved in regulating the expression of genes relevant to PD, RNA-based mechanisms, as well as the effect of toxins and potential epigenetic-based treatments for PD.

Keywords: Acetylation; Epigenetics; Histones; Methylation; Parkinson’s disease; RNA-based epigenetic mechanisms.

Figure 1. A network of Parkinson’s disease (PD) related genes, and the microRNAs that regulate them

Human genome Circos plot [63] showing PD-related genes and regulatory microRNAs. PD related genes are displayed in the outer part of the plot, and microRNAs are displayed in the inner part of the plot. Green = PD genes that have been found using GWAS studies; orange = PD genes that cause familial PD; purple = PD genes that have been found in GWAS studies and that also cause familial forms of PD. Solid grey lines show direct repression of targeted genes by microRNAs; dotted grey lines represent indirect repression by acting on an intermediate mRNA that causes downstream PD gene repression; dotted red lines represent indirect increase of SNCA related brain inflammatory response.

Figure 2. Epigenetic mechanisms involved in α-synuclein pathology

A. NUCLEUS. Methylation of histones promotes histone compression and the formation of condensed heterochromatin. Conversely, acetylation of histones decreases their affinity for DNA allowing nucleosome spacing and heterochromatin to transform into its relaxed form, euchromatin, which is conducive to the transcription of genes such as SNCA. Histone deacetylases (HDAC) remove acetyl group from histone and, as a result, repress gene expression. When DNA methylation occurs at the CpG island in the first intron of SNCA, transcription is also repressed. The enzyme Dnmt1 is involved in maintaining methylation patterns. When intron 1 is de-methylated, transcription of SNCA can proceed. SNCA demethylation can be due to Dnmt1 being sequestered in the cytosplasm by α-synuclein. Histone methylation-acetylation status dynamically changes by complex mechanisms that promote or repress gene transcription depending on cellular conditions and stress. Primary miRNAs are processed by the microprocessor complex, which consists of Drosha and DGCR8. Resulting precursor miRNAs (pre-miR) are transported to the cytoplasm by XPO5. B. CYTOPLASM. SNCA mRNA is translated in the cytoplasm into α-synuclein. In their pathological form α-synuclein monomers are assembled in oligomers and fibrils rich in β-sheets; such fibrils form the basis of the mature Lewy bodies. Pre-miRs are processed by the DICER/TRBP complex into 22bp-miRNA duplexes. The functional strand of a miRNA duplex is incorporated to the AGO2/GW182 complex to generate mature miRISC. MiRISCs containing either miR-7 or miR-153 can bind to the 3’UTR of SNCA mRNA, destabilize the mRNA and induce translational repression. Abbreviations: AAA = poly(A) tail; Ac = acetylated residue; AGO2 = argonaute-2; DICER = endoribonuclease Dicer or helicase with RNase motif; Dnmt1 = DNA (Cytosine-5-)-Methyltransferase 1; HDAC = histone deacetylases; GW182 = trinucleotide repeat-containing gene 6A (TNRC6A); Me = methylated residue; miR = microRNA; miRISC = miRNA-mediated silencing complex; mRNA = messenger RNA; pre-miR = precursor microRNA; pri-miR = primary microRNA; SNCA = Synuclein, Alpha (Non A4 Component Of Amyloid Precursor); TRBP = Transactivation-responsive binding protein; UTR = untranslated region; XPO5 = exportin 5.