Epigenetic Therapies for Treatment of Mental Disorders
Mental health disorders range from anxiety and depression to schizophrenia and dementia, affecting a significant number of people worldwide. Current treatments tend to be short-term and carry high risks of withdrawal symptoms, among other adverse side effects. Epigenetic therapies are relatively recent and novel treatments being studied for their use against mental disorders, targeting illnesses at the source – the genetic code.
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What is Epigenetics?
Genetics is the study of heredity, in which parents pass their genes to their offspring. These are located in the nucleus of each cell in the organism, providing the instructions to building proteins. In turn, they govern the way our bodies work, so defects in our genes are the cause of a large range of diseases. However the incidence of certain disorders that ‘run’ in families cannot be fully explained by genetics2. The most suitable biological mechanism proposed to explain this is epigenetics, originally described by C. H. Waddington, a British evolutionary biologist, in 1942.
Epigenetics (‘epi-‘ is Greek for ‘above’) present a mechanism in which chemical compounds are added to genes, affecting the way they code for proteins. These natural processes are crucial for normal development, especially in cell differentiation, where different proteins are expressed based on the same genome3. This regulation does not involve changes in the genetic code, affecting an individual’s phenotype (the physical expression of genes) but not his/her genotype (the set of genes responsible for that particular characteristic).
In addition, the environment is able to influence epigenetic changes, changes that may even be passed down to later generations4. Studies have shown that depriving the mother of food during early pregnancy increases the risk of coronary heart disease, obesity
From as far back as 1969, DNA methylation has been linked with affecting long-term memory function10. New studies provide further evidence that epigenetic mechanisms are able to regulate long-term neuronal changes. In addition, these changes also affect neuroplasticity, learning capacity, memory
DNA methylation involves inserting a methyl group – a small molecule – into DNA. This occurs at the 5’ position of cytosine in DNA, by an enzyme known as DNA methyltransferases (DNMT). DNMTs are usually active during development, cell division, and differentiation. Therefore it was believed that methylation patterns were stable in differentiated cells. However, new studies show that the mammalian adult nervous system cells undergo significant methylation, contradicting this claim15,16. Inhibiting the DNMT enzyme – and thereby preventing methylation – slows the formation of long-term memories14.
On the back of these results, researchers are starting to examine the role of epigenetics in psychiatric diseases. Faulty epigenetic mechanisms are thought to contribute to depression, psychosis, Alzheimer’s, autism, addiction, etc17-19. Therefore, the development of epigenetic therapies to counteract this is of great value. But a major obstacle in brain drug design is the blood-brain barrier, limiting the number of drugs candidates that target the brain. Due to the nature of this barrier, only molecules with high lipid solubility and low molecular size are able to cross it.
Epigenetic therapies are not exactly new; a number are already approved for the treatment of various cancers20. The problem facing current epigenetic drugs is high toxicity and severe side effects – acceptable in the case of life-threatening conditions, but not viable for diseases requiring a more subtle approach. A few studies show possible therapeutic effects of RG108 for the treatment of mental health illnesses.
RG108 – A Promising Drug Candidate
One promising drug candidate that fits the bill is RG108, a compound exhibiting high selectivity and low toxicity. RG108 is also able to cross the blood-brain barrier and binds to the active site of DNA methyltransferase. This blocks the activity of the enzyme and prevents DNA methylation in the brain21.
Abnormal learning and memory patterns have links to individuals with drug addiction. Synaptic plasticity causes neurons to ‘fire’ too much or too little, changing the strength of such impulses. Drugs such as cocaine can override mechanisms that regulate this, and one such mechanism is the increase in DNA
In depression, stress is thought to have the biggest contributing factor. Recent studies show that depression increases the rate of DNA methylation while decreasing the expression of genes involved in neural plasticity. Researchers were able to modulate stress-induced changes in DNA methylation with RG108, which induced antidepressant-like effects in animal models25.
In another study focusing on obsessive-compulsive disorders (OCD), researchers treated OCD-like behavior (obsessive grooming) in the 3 different mice models to subcutaneous injection of one dose of RG108. RG108 reduced OCD-like behavior in all 3 mice models6. They also studied the role of DNMT methylation on memory and showed direct evidence of altered DNA methylation in a memory-related gene26.
Based on these results, it is clear that mental health outcomes can benefit from epigenetic therapies such as RG108. Other areas that epigenetic drugs could have a large impact are in disorders characterized by memory dysfunction. These include PTSD (overactive recall of traumatic memories) and Alzheimer’s (impaired short-term and eventually long-term memory).
Schizophrenia and mood disorders also show links to epigenetic modifications, where the DNMT1 enzyme is selectively overexpressed in neurons. Brain tissue obtained from individuals who suffered from schizophrenia, bipolar disorder and psychosis exhibited hyper-methylation that decreased the expression of Reelin – a protein involved in normal neurotransmission, memory formation
These results support the hypothesis that mental health disorders can arise from faulty neural processes resulting from epigenetic changes. Further studies are required to better understand these mechanisms, as well as to identify epigenetic biomarkers that represent these diseases. Technology such as genome-wide detection of epigenetic modifications will allow researchers to design safer, more specific and more effective epigenetic therapies. The design and development of these novel therapies provides exciting prospects for the future of mental health management.
- Avery, O.T., C.M. Macleod, and M. McCarty, Studies on the Chemical Nature of the Substance Inducing Transformation of Pneumococcal
Types :Induction of Transformation by a Desoxyribonucleic Acid Fraction Isolated from Pneumococcus Type Iii. J Exp Med, 1944. 79(2): p. 137-58.
- Hotchkiss, R.D., The quantitative separation of purines, pyrimidines, and nucleosides by paper chromatography. J Biol Chem, 1948. 175(1): p. 315-32.
- Holliday, R. and J.E. Pugh, DNA modification mechanisms and gene activity during development. Science, 1975. 187(4173): p. 226-32.
- Waddington, C.H., The epigenotype. 1942. Int J Epidemiol, 2012. 41(1): p. 10-3.
- Painter, R.C., T.J. Roseboom, and O.P. Bleker, Prenatal exposure to the Dutch famine and disease in later life: an overview. Reprod Toxicol, 2005. 20(3): p. 345-52.
- St Clair, D., et al., Rates of adult schizophrenia following prenatal exposure to the Chinese famine of 1959-1961. JAMA, 2005. 294(5): p. 557-62.
- Griffiths, B.B. and R.G. Hunter, Neuroepigenetics of stress. Neuroscience, 2014. 275: p. 420-435.
- Vogelstein, B., et al., Cancer genome landscapes. Science (New York, N.Y.), 2013. 339(6127): p. 1546-1558.
- Egger, G., et al., Epigenetics in human disease and prospects for epigenetic therapy. Nature, 2004. 429(6990): p. 457-63.
- Holliday, R., Epigenetics: a historical overview. Epigenetics, 2006. 1(2): p. 76-80.
- Jarome, T.J., et al., EZH2 Methyltransferase Activity Controls Pten Expression and mTOR Signaling during Fear Memory Reconsolidation. J Neurosci, 2018. 38(35): p. 7635-7648.
- Lubin, F.D., et al., Epigenetic mechanisms: critical contributors to long-term memory formation. Neuroscientist, 2011. 17(6): p. 616-32.
- Wang, Y.J., et al., Histone acetylation in the olfactory bulb of young rats facilitates aversive olfactory learning and synaptic plasticity. Neuroscience, 2013. 232: p. 21-31.
- Miller, C.A. and J.D. Sweatt, Covalent modification of DNA
regulatesmemory formation. Neuron, 2007. 53(6): p. 857-69.
- Goto, K., et al., Expression of DNA methyltransferase gene in mature and immature neurons as well as proliferating cells in mice. Differentiation, 1994. 56(1-2): p. 39-44.
- Feng, J., et al., Dynamic expression of de novo DNA methyltransferases Dnmt3a and Dnmt3b in the central nervous system. J Neurosci Res, 2005. 79(6): p. 734-46.
- Philibert, R.A., et al., MAOA methylation is associated with nicotine and alcohol dependence in women. American journal of medical genetics. Part B, Neuropsychiatric
genetics :the official publication of the International Society of Psychiatric Genetics, 2008. 147B(5): p. 565-570.
- Bonsch, D., et al., Lowered DNA methyltransferase (DNMT-3b) mRNA expression is associated with genomic DNA hypermethylation in patients with chronic alcoholism. J Neural Transm (Vienna), 2006. 113(9): p. 1299-304.
- Nestler, E.J., et al., Epigenetic Basis of Mental Illness. Neuroscientist, 2016. 22(5): p. 447-63.
- Verma, M. and V. Kumar, Chapter 21 – Epigenetic Drugs for Cancer and Precision Medicine, in Epigenetics of Aging and Longevity, A. Moskalev and A.M. Vaiserman, Editors. 2018, Academic Press: Boston. p. 439-451.
- Heerboth, S., et al., Use of epigenetic drugs in disease: an overview. Genetics & epigenetics, 2014. 6: p. 9-19.
- Hyman, S.E., Addiction: a disease of learning and memory. Am J Psychiatry, 2005. 162(8): p. 1414-22.
- Nielsen, D.A., et al., Epigenetics of drug abuse: predisposition or response. Pharmacogenomics, 2012. 13(10): p. 1149-1160.
- Massart, R., et al., Role of DNA methylation in the nucleus accumbens in incubation of cocaine craving. J Neurosci, 2015. 35(21): p. 8042-58.
- Sales, A.J. and S.R. Joca, Effects of DNA methylation inhibitors and conventional antidepressants on mice
behaviourand brain DNA methylation levels. Acta Neuropsychiatr, 2016. 28(1): p. 11-22.
- Genoux, D., et al., Protein phosphatase 1 is a molecular constraint on learning and memory. Nature, 2002. 418(6901): p. 970-5.
- Veldic, M., et al., Epigenetic mechanisms expressed in basal ganglia GABAergic neurons differentiate schizophrenia from bipolar disorder. Schizophrenia research, 2007. 91(1-3): p. 51-61.
- Veldic, M., et al., DNA-methyltransferase 1 mRNA is selectively overexpressed in telencephalic GABAergic interneurons of schizophrenia brains. Proceedings of the National Academy of Sciences of the United States of America, 2004. 101(1): p. 348-353.
- Lardenoije, R., et al., The epigenetics of aging and neurodegeneration. Progress in Neurobiology, 2015. 131: p. 21-64.
- Tordjman, S., et al., Gene?×?Environment Interactions in Autism Spectrum Disorders: Role of Epigenetic Mechanisms. Frontiers in Psychiatry, 2014. 5(53).