From Genetics to Epigenetics: New Perspectives in Tourette Syndrome Research

Abstract

Gilles de la Tourette Syndrome (TS) is a neurodevelopmental disorder marked by the appearance of multiple involuntary motor and vocal tics. TS presents high comorbidity rates with other disorders such as attention deficit hyperactivity disorder (ADHD) and obsessive compulsive disorder (OCD). TS is highly heritable and has a complex polygenic background. However, environmental factors also play a role in the manifestation of symptoms. Different epigenetic mechanisms may represent the link between these two causalities. Epigenetic regulation has been shown to have an impact in the development of many neuropsychiatric disorders, however very little is known about its effects on Tourette Syndrome. This review provides a summary of the recent findings in genetic background of TS, followed by an overview on different epigenetic mechanisms, such as DNA methylation, histone modifications, and non-coding RNAs in the regulation of gene expression. Epigenetic studies in other neurological and psychiatric disorders are discussed along with the TS-related epigenetic findings available in the literature to date. Moreover, we are proposing that some general epigenetic mechanisms seen in other neuropsychiatric disorders may also play a role in the pathogenesis of TS.

Keywords: DNA methylation; Tourette Syndrome; epigenetics; genetics; neurological disorders; non-coding RNA; psychiatric disorders.

Figure 1

Overview of common covalent epigenetic modifications. A schematic nucleosome and examples of potential epigenetic modifications are shown. The histone octamer is represented in a cylindrical form with one pair of histones H3/H4 indicated. The protruding H3 histone tail and DNA are indicated in orange and purple, respectively. Oppositely, histone and DNA modifications are shown in purple and orange. The functional roles of histone modifications are indicated in colored boxes. The enzyme families catalyzing the modifications are listed in boxes below. The enzymatic links between the different cytosine modifications are shown in the upper right corner of the figure.

Figure 2

The relationship between epigenetic modifications and intermediary metabolism. Glycolysis, lipid metabolism, citric acid cycle, amino acid metabolism, and folate/SAM cycles are tightly linked to epigenetic modifications (shown in the middle), since their products and cofactors (shown in red) are substrates of enzymes catalyzing the epigenetic modifications. Acetyl-coenzyme A and NAD contribute to histone acetylation and deacetylation, respectively. Methyl groups and alfa-ketoglutarate participate in the methylation and demethylation of both histones and DNA. NAD: nicotinamide adenine dinucleotide, THF: tetrahydrofolate, SAH: S-adenosylhomocysteine, SAM: S-adenosylmethionine.

Figure 3

miRNA biogenesis. MicroRNA (miRNA) genes are transcribed as primary miRNAs (pri-miRNAs) by RNA polymerase II (Pol II) in the nucleus. The long pri-miRNAs are cleaved by Microprocessor, which includes DROSHA and DiGeorge syndrome critical region 8 (DGCR8), to produce precursor miRNAs (pre-miRNAs), which are then exported to the cytoplasm by Exportin 5 and further processed by the DICER/TRPB complex to produce an miRNA duplex. One strand of the mature miRNA (the guide strand) is loaded into the miRNA-induced silencing complex (RISC) mediating gene suppression by targeted mRNA degradation or translational repression.