Autoimmune Thyroid Disease

An Unfortunate and Lengthy Adventure in Misdiagnosis

DNA hypermethylation and GABA

with 4 comments

Following on from a previous post in which exposure to methylation supplements like folate during pregnancy appears to increase the risk of food chemical intolerance symptoms in children by causing DNA hypermethylation, there are also hints that DNA hypermethylation can be harmful in a different way:

ScienceDaily (Aug. 1, 2008) β€” Autopsies usually point to a cause of death but now a study of brain tissue collected during these procedures, may explain an underlying cause of major depression and suicide.

The international research group, led by Dr. Michael O. Poulter of Robarts Research Institute at The University of Western Ontario and Dr. Hymie Anisman of the Neuroscience Research Institute at Carleton University, is the first to show that proteins that modify DNA directly are more highly expressed in the brains of people who commit suicide.

These proteins are involved in chemically modifying DNA in a process called epigenomic regulation. The paper is published in Biological Psychiatry.

The researchers compared the brains of people who committed suicide with those of a control group who died suddenly, from heart attacks and other causes. They found that the genome in depressed people who had committed suicide was chemically modified by a process that is normally involved in regulating the essential characteristics of all cells in the body. As Poulter explains, “We have about 40,000 genes in every cell and the main reason a brain cell is a brain cell is because only a small fraction of the genes are turned on. The remaining genes that are not expressed are shut down by an epigenetic process called DNA methylation.”

The rate of methylation in the suicide brains was found to be much greater than that of the control group. Importantly, one of the genes they studied was shown to be heavily chemically modified and its expression was reduced. This particular gene plays a major role in regulating brain activity. “Interestingly, the nature of this chemical modification is long term and hard to reverse, and this fits with depression,” says Poulter.

“The whole idea that the genome is so malleable in the brain is surprising. Finding that epigenetic mechanisms continue to influence gene expression is pretty unusual,” says Poulter, who is also a professor in the Department of Physiology and Pharmacology at Western’s Schulich School of Medicine & Dentistry. “These observations open an entirely new avenue of research and potential therapeutic interventions.” The research was funded through the Canadian Institutes of Health Research. Autopsies Reveal Changes To DNA In Major Depression And Suicide

The gene in question that becomes hypermethylated is the GABA-A receptor. Here’s the associated abstract:

BACKGROUND: Epigenetic mechanisms may be involved in the reprogramming of gene expression in response to stressful stimuli. This investigation determined whether epigenetic phenomena might similarly be associated with suicide/depression.

METHODS: The expression of DNA methyltransferase (DNMT) mRNA was assessed in several brain regions of individuals who had committed suicide and had been diagnosed with major depression relative to that of individuals who had died suddenly as a result of factors other than suicide.

RESULTS: The DNMT gene transcripts’ expression was altered in several brains regions of suicides, including frontopolar cortex, amygdala, and the paraventricular nucleus of the hypothalamus. Importantly, an increase of both mRNA and protein expression was found in the frontopolar cortex. In addition, although transcript abundance of various forms of DNMT was highly correlated in normal control subjects, this coordination of DNMT isoform expression was diminished in suicide brain. Further, within the frontopolar cortex, gene-specific aberrations in DNA methylation were apparent in the gamma-aminobutyric acid (GABA)(A) receptor alpha1 subunit promoter region, the transcript of which is underexpressed in suicide/major depressive disorder (MDD) brains. Indeed, three cytosine/guanosine sites were hypermethylated relative to control subjects. Finally, we found that DNMT-3B mRNA abundance was inversely correlated to alpha1 mRNA abundance.

CONCLUSIONS: These data show that DNMT mRNA expression was altered in suicide brain, and this change in expression in the frontopolar cortex was associated with increased methylation of a gene whose mRNA expression has previously been shown to be reduced. These observations suggest that epigenetic mechanisms may be associated with altered gene expression in suicide/MDD. GABAA receptor promoter hypermethylation in suicide brain: implications for the involvement of epigenetic processes

Why is this important to failsafers?

Well, ketosis (low carbing) raises GABA levels. GABA levels are thought to be deficient in people with bipolar disorder and autism. The manic/depressive swings associated with bipolar disorder are thought to be caused by the subsequent deregulation of glutamate. During manic phases, glutamate levels are too high, and during depressive phases, glutamate levels are too low. I will write more on this subject soon.

Salicylates are thought to interfere with DNA methylation – they are thought to protect against DNA hypomethylation. Does this go as far as increasing the risk of DNA hypermethylation? It would not surprise me.

In the brain, salicylates are thought to act on excitatory NMDA receptors (a form of glutamate receptor). They are also thought to block GABA release by acting on calcium channels.

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Written by alienrobotgirl

29 October, 2008 at 1:14 am

Posted in Methyl Donors

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4 Responses

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  1. Hi,

    I would first like to say, I appreciate this entire blog immensely! πŸ™‚

    I am wondering how you feel about fresh goat cheeses such as chevre. Do you find they are particularly reactive? Would they have a high amine content or glutamates (sorry, I am just beginning to understand the food-chemical connection…I have found you from the HO forum). I feel sometimes they help to increase my concentration (maybe this is the calcium/gaba connection?), but the following day I am constipated and slightly irritable.

    I would like to try fresh goat milk but it is hard to find a decent brand where I am. I do, however, feel better definitely with a ketogenic diet, and especially if I remain on A2 dairies, although I can handle cow cream but not cow butter and actually eggs are giving me some nausea and brain fog for this moment.

    How low carb you recommend for bi-polar people to remain? Would you say a slightly asperger person could follow the same advise? Is it sufficient to have your carbohydrates all come from the lactose in fresh dairy if you are getting enough of your other nutrients?

    Sorry if this was quite scattered…must still be the food chems πŸ˜‰

    Thank you very much for your time and this enormous database of personal wisdom and experience and information.

    mc1r

    1 November, 2008 at 5:04 pm

  2. Hi MC1R, do you have red hair perchance? πŸ˜€

    Unfortunately I find chevre a bit too aminey, though not being particularly sensitive to opioids I tolerate regular cottage cheese, cream cheese and mascarpone, which seem to be lower in amines. I don’t know if it’s possible to make your own!

    I would say low carb enough to be ketogenic, i.e. below about forty grams, maximum of seventy grams.

    When I am low carbing, I get all of my carbohydrate from fresh dairy. It’s pretty difficult to give yourself a deficiency in anything on a diet of meat and dairy (though eggs and the occasional potato too would be better). Milk actually contains a significant amount of vitamin C. The only thing I would say is if you get a lot of calcium, you might also need some supplemental magnesium, and possibly iron, as there are antagonistic effects.

    Aalienrobotgirl

    8 November, 2008 at 12:07 am

  3. I should also say… re: aspergers,

    ketosis makes a big difference to my mood swings, which are a feature of aspergers (seems like everyone with aspergers has a bipolar relative), but not a huge difference to my inherent introversion. I am calmer and more clear-headed with a much higher tolerance for stress when in ketosis, but I’m only slightly more likely to come out of my shell.

    alienrobotgirl

    8 November, 2008 at 12:41 am

  4. Thank you!

    Yaya you are correct about my name reference ^-^ lol. In my family, we are very mixed so I am unusual for this trait. But I must say it is quite a relief to start and find all of this mess of genetics that I am, hehe (I found you long ago but was undisciplined to begin elimination diet properly. I try with the optimal way with some unhealthy liberties ;). I wish I were not sensitive to the opioids, that would likely make failsafe perhaps less restrictive for me. Do you tolerate the cow yoghurt? Or only the sheep/goat? I read of the messages by Elena who also has issue with eggs. Do you have any thoughts about this? I am wondering too if it is the sulfur. Just thinking of them makes me have nausea. It is bad as they are quite good for you! I also have bowel disorder that runs in my grand family so I worry I have preliminary stages of protein malabsorbing in the upper intestine. And too much fats can mess with my large intestine/colon.
    Ya, ketosis does help tremendously with mood stability, but my concentration and motivation still inconsistently. I hope to fix this but it is hard it seems. I can fall into deep depressive states too and so you have my understanding completely of this. I am sorry you can not just keep always writing lovely stories for us to read! The creative impulse is a wonderful thing πŸ™‚

    anyway…
    …so much to balance…it overwhelms !

    Be well and thank you again for your time.

    mc1r

    10 November, 2008 at 12:22 am


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