Invest in ME Conference 12: First Class in Every Way
OverTheHills wraps up our series of articles on this year's 12th Invest in ME International Conference (IIMEC12) in London with some reflections on her experience as a patient attending the conference for the first time.
Discuss the article on the Forums.

Two possible causes of undermethylation and Is PARP draining NAD?

Discussion in 'General ME/CFS Discussion' started by Kimsie, Jan 27, 2015.

  1. Kimsie

    Kimsie Senior Member

    Messages:
    397
    Likes:
    404
    The following post is rather technical in some aspects. Sorry about that, I just can’t think of another way to get my ideas across. The basic idea is that undermethylation can be a result of an increased need for thyroid or from a low NAD pool in conditions of oxidative stress. I haven’t been able to figure out what might cause overmethylation, except that it might have something to do with insufficient glycine N-methyltransferase.

    According to my hypothesis, there is a problem maintaining a sufficient NAD pool in the mitochondria for energy production. At this time I am entertaining the idea that this is due to an increase in PARP activity to repair DNA damage due to the oxidative stress, since PARP consumes NAD. The increase in flux through the NAD pool might explain the increase in uric acid in some people who might have a less active purine salvage pathway, or the increase in uric acid may be due to an increase in the production of uric acid to act as an antioxidant.

    Sirtuins decrease gene expression and require NAD to be active. If a person is having difficulty in the pathway to make purines, they may not be able to make sufficient purines for NAD and ATP production, which can not only affect energy production but could lower the sirtuins’ ability to deactylate histones, which could lead to undermethylation of histones in susceptible people.

    There is a connection between thyroid hormones and oxidative stress, but does oxidative stress increase the need for thyroid hormones or does thyroid hormone increase oxidative stress? When a person has high thyroid hormones and high oxidative stress, is the thyroid causing the oxidative stress, or is it there to try to get rid of it? When a person has low thyroid and high oxidative stress, is the oxidative stress high because they can’t supply enough thyroid?

    Sirt1 helps control (lower) TSH, so if thyroid is needed to help control oxidative stress, an increased need for thyroid could lower sirt1 activity.

    Sirt1 and LSD1, a histone demethylase, work together in an enzyme complex called a corepressor complex. It appears to me from our experience that the LSD1 is upregulated when sirt1 is downregulated which would make a lot of sense because LSD1 activates and sirt1 represses expression. This can lead to an undermethylation of some histones causing various symptoms, causing various problems, such as so called “mental illnesses” due to an increase in the production of neurotransmitter transport proteins leading to a condition of insufficient neurotransmitters in the synapses. At this time I don’t know what other symptoms it can cause, but there may be symptoms from an increase in other enzymes, too, and also draining of various vitamins and minerals due to hyperactivity of some pathways.

    Which pathways in the body that are affected enough to cause symptoms depends on the genetic weaknesses of the individual.

    In this undermethylated condition taking thyroid can increase sirt1 and thus decrease LSD1 activity since bypassing the need for TSH decreases the need for sirt1. An increase in thyroid will temporarily increase sensitivity to some of the neurotransmitters, so it can have immediate effects that could be good or bad depending on what a person's symptoms are. The long term effects should be to lower gene expression and raise sirt1.
     
    Last edited: Jan 28, 2015
  2. wastwater

    wastwater Senior Member

    Messages:
    856
    Likes:
    486
    uk
    Is this the same parp as in parp inhibitors connected to brca2
     

See more popular forum discussions.

Share This Page