Mental illnesses – parts of a sole huge illness

Psychiatric genetics is basically a research program with no connection to treatment except for very rare high impact genetic loci.

An endophenotype refers to a characteristic that is not easily observed on the surface. Almost all mental illnesses are due to epigenetic dysregulations. The endophenotypes of psychiatric illnesses would be the sets of epigenetic marks that are associated with given mental illnesses. The variability in symptoms in given illnesses is due to variations on the basic sets of epigenetic marks associated with such illnesses.

Mental illnesses arise due to dysregulation of TET enzymes and JmnjC-domain containing .proteins with TET enzymes involved in DNA demethylation and JmnjC-domain containing proteins involved in histone demethylation. Histone acetylation which requires acetyl-coenzyme A also plays a part.

Though dysregulation of TET enzymes and JmnjC-domain proteins and dysregulation of acetyl-coenzyme A are fundamental to all mental illnesses various mental illnesses separate from each other as spatially closely associated pathways fall together. Use the pathways or lose the pathways. And as these are epigenetic dysregulations, pathways that are lost are spatially localized to various organs and/or regions of organs, for example, regions of the brain. Trying to distinguish mental illnesses by examining genes is pointless.

Trying to isolate endophenotypes so as to enhance treatments is not necessary. With basic epigenetic dysregulations addressed almost all mental illnesses. can be treated. A treatment that addresses dysregulation of TET enzymes and JmnjC-domain proteins and dysregulation of acetyl-coenzyme A could address all mental illnesses.

Any reprogramming of youthful methylation patterns in humans would require that TET enzymes be re-regulated first

l

Sinclair et al. using the eye as a model CNS tissue, showed that ectopic expression of Oct4, Sox2 and Klf4 genes in mouse retinal ganglion cells restores youthful DNA methylation patterns and transcriptomes, promotes axon regeneration after injury, and reverses vision loss in a mouse model of glaucoma and in aged mice. The beneficial effects of OSK-induced reprogramming in axon regeneration and vision require the DNA demethylases TET1 and TET2.

However, I have been arguing in papers (see Treatment-resistant schizophrenia: focus on the transsulfuration pathway and A disease-modifying treatment for Alzheimer’s disease: focus on the transsulfuration pathway) and on this blog that TET enzymes are the very enzymes that are dysregulated in many chronic illnesses, which results in various chronic illnesses possessing a range of phenotypic expressions. Ectopic expression of OCT4, KLF4 and SOX2 alone would not work in aged humans and/or ill humans as TET enzymes are dysregulated in aged and/or ill humans.

TET enzymes are iron and 2-oxoglutarate dependent dioxyegenases. Fixing TET enzymes could be a key part of the treatment of a range of chronic illness and would be a lot simpler and safer than systematic ectopic expression of OCT4, KLF4 and SOX2 in humans. A lot of methylation changes acquired during aging must be beneficial. Systematically turning back the clock to 18 or so would not be desirable .’Just’ fixing TET enzymes would allow desirable methylations to occur but would allow DNA demethylations of undesirable DNA methyations. Clearly fixing TET enzymes would be a required first step prior to any genetic engineering of humans to restore youthfulness given that such genetic engineering was feasible and desirable.

Can deleterious epigenetic changes be reversed by supplemental alpha ketoglutarate?

l

TET enzymes are 2-oxoglutarate dependent.enzymes that are instrumental in DNA demethylation. JmjC domain-containing proteins, which are 2-oxoglutarate dependent.enzymes, demethylate histones.

Research indicates that 2-oxoglutarate by affecting TET and Jmjc domain-containing proteins can have epigenetic effects reversing epigenetic changes arising from dysregulation of the tricarboxylic acid (TCA) cycle. The TCA cycle synthesizes 2-oxoglutarate.

I have been stressing in this blog that with a dysregulation of iron-sulfur cluster formation there is a dysregulation of aconitase which is an iron-sulfur protein early in the TCA cycle With aconitase dysregulated the TCA cycle is dysregulated. Another enzyme in the TCA cycle, succinate dehydrogenase, also has iron-sulfur clusters.

Could deleterious epigenetic changes in humans, due to dysregulation of the TCA cycle, be reversed by supplemental alpha-ketoglutarate? That has not yet been established.

2-oxoglutarate-dependent dioxygenases are involved in aging, 2-oxoglutarate could be a longevity supplement. A rule of thumb in regards to longevity supplements is never take a longevity supplement for longevity that does not have immediate positive benefits as absent immediate positive benefits knowing whether one is going in the correct direction is unknowable . If 2-oxoglutarate proves to be useful in the treatment of various neurological illnesses but also increases longevity so much the better.

Mutations of genes for enzymes in the TCA cycle can inhibit TET enzymes

TET enzymes, which demethylate DNA, are 2-oxoglutarate dependent enzymes. 2-oxoglutarate is synthesized by the citric acid cycle. Mutation of genes for enzymes in the citric acid cycle can inhibit TET enzymes, thereby dysregulating epigenetic mechanisms.

Iron regulates enzymes is the TCA cycle. Dysregulation of iron metabolism could dysregulate the TCA cycle resulting in epigenetic dysregulations.

A new disease class – Epigenetic Disorders

There are infectious diseases subdivided into bacterial and viral diseases, there is cancer where there are many sorts of cancer, there is heart disease, lung disorders  etc. There could be a new disease class. There could  be epigenetic disorders where there is common origin for a wide range of epigenetic disorders. With epigenetic mechanisms  dysregulated many different diseases can arise as there are many different ways genes and histones can become inappropriately methylated.  My idea is that a dysregulation of aconitase 1 can dysregulate iron metabolism and decrease 2-oxogularate synthesis which will in turn dysregulate TET enzymes, which demethylate DNA,  and dysregulate Jumonji domain-containing proteins, which demethylate histones.   Dysregulation of  TET enzymes and dysregulation of Jumonji domain-containing proteins  can play out many different ways in terms of inappropriate DNA methylation and inappropriate histone methylation whereby many different diseases can arise. Though many different diseases can arise from dysregulations of aconitase 1, iron metabolism and 2-oxoglutarate synthesis prevention of a range of illnesses could be achieved by the same treatment. For example, a treatment than prevents schizophrenia could also prevent Alzheimer’s disease and Parkinson’s disease. The Treatment presented in the Treatment section is not ready for home use, however, a Moon shot would not be necessary to get the treatment to a state where family doctors could prescribe a treatment which would prevent a range of chronic illnesses from schizophrenia, to Alzheimer’s disease, to Parkinson’s disease. What is needed is a launch ten weather balloons into the high atmosphere then collect and analyze data kind of effort.