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Review
. 2023 Apr 2;24(7):6645.
doi: 10.3390/ijms24076645.

Unraveling the Complex Interplay between Alpha-Synuclein and Epigenetic Modification

Naoto Sugeno  1 , Takafumi Hasegawa  1
Affiliations
Review

Unraveling the Complex Interplay between Alpha-Synuclein and Epigenetic Modification

Naoto Sugeno et al. Int J Mol Sci. .

Abstract

Alpha-synuclein (αS) is a small, presynaptic neuronal protein encoded by the SNCA gene. Point mutations and gene multiplication of SNCA cause rare familial forms of Parkinson's disease (PD). Misfolded αS is cytotoxic and is a component of Lewy bodies, which are a pathological hallmark of PD. Because SNCA multiplication is sufficient to cause full-blown PD, gene dosage likely has a strong impact on pathogenesis. In sporadic PD, increased SNCA expression resulting from a minor genetic background and various environmental factors may contribute to pathogenesis in a complementary manner. With respect to genetic background, several risk loci neighboring the SNCA gene have been identified, and epigenetic alterations, such as CpG methylation and regulatory histone marks, are considered important factors. These alterations synergistically upregulate αS expression and some post-translational modifications of αS facilitate its translocation to the nucleus. Nuclear αS interacts with DNA, histones, and their modifiers to alter epigenetic status; thereby, influencing the stability of neuronal function. Epigenetic changes do not affect the gene itself but can provide an appropriate transcriptional response for neuronal survival through DNA methylation or histone modifications. As a new approach, publicly available RNA sequencing datasets from human midbrain-like organoids may be used to compare transcriptional responses through epigenetic alterations. This informatic approach combined with the vast amount of transcriptomics data will lead to the discovery of novel pathways for the development of disease-modifying therapies for PD.

Keywords: alpha-synuclein; bioinformatics; epigenome; organoids.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Changes in methylation status of CpG islands located in SNCA intron 1. (A) The indexed number of CpG sites is based on the report by Jowaed et al. [42,43,44,45,46,47,48,49,50,51]. The numbering of CpG sites is not identical in each study and is, therefore, corrected and displayed accordingly. Differences in methylation rates of CpG sites are compared between Parkinson’s disease (PD) or dementia with Lewy bodies (DLB) and healthy subjects or disease controls. The analyses are varied, but do not show consistent results. Nevertheless, CpG numbers 8 and 18 are likely more sensitive to the methylation modulating system or nuclear environment. (B) Schematic presentation of the human SNCA gene. Rep1, a dinucleotide repeat site, the length of which affects SNCA expression, located approximately 10 kb upstream from the start codon in exon 2. The CpG island located in intron 1 includes 23 CpG sites. Primer sequences for pyrosequencing by Jowaed et al. are underlined. The abbreviations used are as follows: PWBCs, peripheral white blood cells; PBMC, peripheral blood mononuclear cells.
Figure 2
Figure 2
Schematic illustration of post-translational modifications of histone proteins affected by alpha-synuclein (αS). Lysine methylation has different functions depending on its residues. Methylation (Met) of H3 lysine 9 (K9), lysine 27 (K27), and H4 lysine 20 (K20) is often associated with transcriptional repression. In contrast, the methylation of H3 lysine 4 (K4), lysine 36 (K36), or lysine 79 (K79) is largely responsible for transcriptional activation. In addition, histone acetylation (Ac) usually promotes gene expression. Combined stimulation with αS and retinoic acid (RA) enhances K9 methylation of H3 through the activation of euchromatic histone lysine N-methyltransferase 2 (EHMT2). In addition, the inactivation of lysine acetyltransferases (KATs) decreases histone acetylation. The other transcriptional active mark, K36 methylation of H3, is also downregulated by αS. Both increased repressive signals and disruption of active marks result in the transcriptional repression of downstream genes.
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