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From Genetics to Epigenetics: New Perspectives in Tourette Syndrome Research.

Pagliaroli L, Vető B, Arányi T, Barta C - Front Neurosci (2016)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis UniversityBudapest, Hungary; Research Centre for Natural Sciences, Institute of Enzymology, Hungarian Academy of SciencesBudapest, Hungary.

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.

No MeSH data available.


Related in: MedlinePlus

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.
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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.

Mentions: Therefore, it is not surprising that enzymes catalysing the addition or removal of covalent post-translational modifications of histones and DNA are closely linked to intermediary metabolism (Figure 2). To acetylate lysine residues, HAT enzymes use acetyl-CoA, a key molecule in carbohydrate and fat metabolism. Class III histone deacetylases (Sirt) need NAD+ for their activity (Vaquero et al., 2007). High level of energy intake leads to hyperacetylated histones, while low energy intake favors histone hypoacetylation. Methylation of histones and DNA needs S-adenosyl-methionin (SAM) as a cofactor, the methyl donor in biochemical reactions. The reaction also needs folate to regenerate SAM. The TeT (Ten-eleven Translocase) enzymes are oxygenases, which catalyse the demethylation reaction of DNA through the formation of 5-hydroxy-methyl cytosine. Jumonji family of histone demethylases have a similar reaction mechanism (Chen et al., 2006). Both TeT and Jumonji enzymes use α-ketoglutarate as a co-factor, which is a key metabolite of the citric-acid cycle. Enzymes catalysing the formation of α-ketoglutarate are different isoforms of isocitrate dehydrogenase (IDH). Some of the IDHs are mitochondrial, others are cytosolic, and they depend on NADP and NAD, respectively. SNPs of these enzymes are associated with TS (see later), while their mutations show frequent occurrence in tumors (gliomas, AML) (Dang et al., 2010). The gain-of-function mutant enzymes catalyse the formation of 2-hydroxyglutarate (2-HG), a potent inhibitor of demethylases. Altogether these data suggest a tight link between environmental factors and epigenetic modifications.


From Genetics to Epigenetics: New Perspectives in Tourette Syndrome Research.

Pagliaroli L, Vető B, Arányi T, Barta C - Front Neurosci (2016)

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.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4940402&req=5

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.
Mentions: Therefore, it is not surprising that enzymes catalysing the addition or removal of covalent post-translational modifications of histones and DNA are closely linked to intermediary metabolism (Figure 2). To acetylate lysine residues, HAT enzymes use acetyl-CoA, a key molecule in carbohydrate and fat metabolism. Class III histone deacetylases (Sirt) need NAD+ for their activity (Vaquero et al., 2007). High level of energy intake leads to hyperacetylated histones, while low energy intake favors histone hypoacetylation. Methylation of histones and DNA needs S-adenosyl-methionin (SAM) as a cofactor, the methyl donor in biochemical reactions. The reaction also needs folate to regenerate SAM. The TeT (Ten-eleven Translocase) enzymes are oxygenases, which catalyse the demethylation reaction of DNA through the formation of 5-hydroxy-methyl cytosine. Jumonji family of histone demethylases have a similar reaction mechanism (Chen et al., 2006). Both TeT and Jumonji enzymes use α-ketoglutarate as a co-factor, which is a key metabolite of the citric-acid cycle. Enzymes catalysing the formation of α-ketoglutarate are different isoforms of isocitrate dehydrogenase (IDH). Some of the IDHs are mitochondrial, others are cytosolic, and they depend on NADP and NAD, respectively. SNPs of these enzymes are associated with TS (see later), while their mutations show frequent occurrence in tumors (gliomas, AML) (Dang et al., 2010). The gain-of-function mutant enzymes catalyse the formation of 2-hydroxyglutarate (2-HG), a potent inhibitor of demethylases. Altogether these data suggest a tight link between environmental factors and epigenetic modifications.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis UniversityBudapest, Hungary; Research Centre for Natural Sciences, Institute of Enzymology, Hungarian Academy of SciencesBudapest, Hungary.

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.

No MeSH data available.


Related in: MedlinePlus