Letter to the Editor

Epigenetic Influences on Autism Spectrum Disorders: Novel Targets for Treatments

Yulia A Volkova1, Isaac Opoku-Asare2, Luc M Oke3, Sudhakar Pemminati4 and Richard M Millis5*
1Department of Clinical Medicine, American University of Antigua College of Medicine, St. John’s, Antigua and Barbuda
2Division of Cardiology, Department of Internal Medicine, Howard University Hospital, Washington, DC 20060, USA
3American Center for Investigative Cardiology, 8630 Fenton Street Suite 522, Silver Spring, MD 20910, USA
4Departments of Pharmacology &Manipal University, American University of Antigua College of Medicine, USA
5Department of Medical Physiology, American University of Antigua College of Medicine, USA


*Corresponding author: Richard Mark Millis, Department of Medical Physiology, American University of Antigua College of Medicine, USA


Published: 13 Nov, 2017
Cite this article as: Volkova YA, Opoku-Asare I, Oke LM, Pemminati S, Millis RM. Epigenetic Influences on Autism Spectrum Disorders: Novel Targets for Treatments. Ann Pharmacol Pharm. 2017; 2(26): 1134.

Letter to the Editor

Complementary and alternative medical treatments are proposed for autism spectrum disorders (ASDs) [1]. ASDs result from complex environment-gene interactions. An epigenetic mechanism that appears to play a role in ASDs involves low activity of methyl-CPG-binding protein-2 (MECP2) at CpG islands in genes within cells localized to the frontal cerebral cortex, resulting in hypermethylation of DNA. Hypomethylationdue to reduced availability of S-adenosyl methionine (SAM), an important donor of methyl groups, is shown to occur in mothers of children affected by ASDs [2]. Low activity of MECP2 is associated with disinhibition of his tone deacetylase-1 (HDAC1) which inhibits the chromatin condensation required for silencing of genes and limiting protein synthesis. It is hypothesized that down regulation of HDAC1 by valproic acid and of glycogen synthase kinase-3beta (GSK3β) by lithium may upregulate one of the main eukaryotic cell differentiation signaling mechanisms, the wingless nt-1 proto-oncogene (Wnt) pathway [3].
Such stimulation of the Wnt pathway is shown to cause accumulation of β-catenin in the cytosol with translocation to the nucleus. In the nucleus, β-catenin activates mRNA transcription and protein synthesis. This enhancement of protein synthesis may produce the conditions for developing the macrocephaly and increased number of cerebral cortical minicolumns often observed in brains from individuals diagnosed with ASDs [4]. DNA methyl transferase (DNMT) is shown to methylate and down regulate the oxytocin receptor gene resulting in low oxytocin activity. Low oxytocin activity is purported to upregulate androgen receptors in the brain which mediate high arousal inputs to the amygdyla, associated with antisocial behaviors after exposure to environmental stressors. This sequence of events may be a basis for the predominance of males with antisocial behaviors and/or with ASDs.5 A related epigenetic mechanism involves phosphorylation of his tone H3 by protein kinase C beta (PKC3β) which is known to activate lysine demethylase- 1(LSD1), a his tone methyl transferase (HMT) that prevents de methylation of his tone H3K4, also purported to mediate androgen receptor stimulation of high arousal inputs to the amygdyla. Various environmental and nutritional conditions acting as pro- or anti-autism factors targeting epigenetic mechanisms may further suggest novel targets and alternative, complementary strategies for decreasing the prevalence of ASDs.


Supported

Supported in part by a training fellowship awarded to Yulia A. Volkova, MD by the American Center for Investigative Cardiology.