Methylation and Neurotransmitters

Key technical points:

  • Histones and genes on DNA have both acetyls (Ac) and methyls (Me) attached which affect gene transcription.
  • Nutrient therapy and nutrition in general can affect histone methylation more easily albeit slowly but individual DNA methylation is more permanent at the moment. This can be changed during early pregnancy in the fetus or later in life or through oxidative stress effects on DNA , but this latter is apparently a more random effect.
  • The balance of Ac and Me at any DNA area will determine transcription. On DNA itself, more Me than Ac is an epigenetic “off” switch to transcription. The gene will not be expressed into a protein or enzyme, or to a lesser degree.
  • The histones also have Ac and Me, and this regulates general chromatin open/closed configuration. Here, more Me than Ac creates a closed configuration. Closed means a bunch of genes together in the affected histones are less likely to be expressed.
  • Therefore more Me than Ac generally tends to switch off genes, either individually on DNA or in bunches at the histones. These effects combine to make some genes more expressed than others depending on the overall result of methylation and acetylation at each point.
  • Therefore, overmethyators (OM) would generally express less of the genes which reduce dopamine and serotonin so they would have “too much” with all the mental health problems associated with that. With undermethylators (UM) it’s the opposite, with different kinds of problems, but these all end up lumped together as “depression” or “schizophrenia” in the DSM diagnostic system.
  • Folates reduce methylation and promote gene expression. OMs will do better, UMs will do worse. This is despite folates generally adding methyls to the methylation cycle hence the “folate paradox”.

 

Images below from a powerpoint presentation By Dr Walsh

http://www.walshinstitute.org/uploads/1/7/9/9/17997321/cam_london_keynote_dr_walsh_11_07_15_final.pdf

 

In the 1950s Dr Hoffer observed initially the success of niacins and folates treatments in people with the then current schizophrenia diagnosis, and deleterious effects of methionine. This was not satisfactorily explained and constituted a stumbling block in adoption of his treatment methods. Later came refinements from further clinical research which distinguished the two depression/psychosis groups of under/overmethylation (UM/OM) or histadelia/histapenia which are opposite in their treatments and contraindications.

Signs and symptoms of UM are those of the negative symptoms of schizophrenia (catatonia, etc) while those in OM are the positive ones (hallucinations, etc). These are consistent with the dopamine effects which are conventionally posited for these illnesses, which are seen as umbrella terms for diverse biochemical conditions according to the Walsh/Pfeiffer/Hoffer paradigm.
It’s really the methylation aspect which is key to the understanding of this it seems. There is a recently¬† developing field devoted to nutrigenomics as they pertain to Single Nucleotide Polymorphysims (SNPs) on the DNA of methylation pathway enzymes which concords with this except in the key area of Mental Health/brain disorders which is the focus of the Walsh Research Institute (WRI).
Depressed or psychotic people with UM diagnoses respond well to SAMe or its precursor methionine whereas similar DSM labeled people with OM diagnoses react very badly, akin to the heretofore unpredicatble SSRI response. SAMe is the major methyl donor to the methylation cycle and as such it was thought that this increased serotonin and dopamine levels, UM having too little and OMs having too much.
There was the puzzle of the folate paradox however, as folates are generally methyl donors and they tend to make UMs worse when the opposite effect is observed. With the advent of epigenetics came the answer: It really seems to be about DNA methylation marker effects on the reuptake proteins and histone configuration which are dominant in their effect.
The focus has shifted to the greater effect of reuptake over production, as folates are seen to remove methyl markers from individual gene markers and histone tails and therefore promote the expression of these reuptake proteins causing lower levels in the synapses. This is, of course, inference from observed clinical effects and current general research. Niacins, on the other hand, cause overall methyl levels to lower and are seen to have a similar effect on the histone tails.
This is why histadelia which is diagnosed from high levels of the indirect Whole Blood Histamine (WBH) marker is now known in Walsh terminology as undermethylation, and histapenia (low levels of WBH) is know as overmethylation or even more simply folate deficiency (folates are the main treatment). When dealing with the Lynch/Yasko paradigms the terminology can get tricky but this is resolved when one remembers this is in the separate domain of brain function and neurotransmitters.
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