ER Stress, Protein Misfolding, TUDCA.

Discussion in 'Other Research' started by Remy, Mar 21, 2016.

  1. Remy

    Remy Administrator

    We hear a lot about oxidative stress and mitochondrial dysfunction in MECFS, but less about another problem that I think is commonly experienced and leads to symptoms...endoplasmic reticulum stress and the unfolded protein response.

    Wikipedia has a reasonable introduction to the endoplasmic reticulum but in a nutshell, it is an organelle present in all cells that feature a nucleus. It consists of an outer membrane studded with ribosomes that make proteins and an inner membrane that is involved in lipid synthesis, steroid hormone production (cortisol an sex hormones) and detoxification.

    It is intricately involved with the cell membrane...the very same cell membrane that is often damaged in people with chronic illness and the same cell membrane we try to rebuild by taking proper amounts of essential fatty acids.

    If the endoplasmic reticulum isn't functioning properly, the proteins synthesized are misfolded and can't do the job for which they are intended properly. Drugs do this, infections do this, basically anything that causes stress to the organism.

    But there are ways to mitigate the damage and help correct the protein folding response. Bile acids are critical for the proper protein folding response...and you can supplement them.

    TUDCA is one such example found over the counter. It is synthesized from UDCA in the intestines by bacteria and then bound to a taurine atom. Unlike most bile acids, it's water soluble and exerts a protective effect on the liver and gallbladder when detox is slow and the fat based bile acids are backed up (cholestasis). TUDCA has been studied the most for fatty liver disease and they found a protective effect equivalent to the currently FDA prescribed drug, UDCA, which makes sense since it is essentially the same thing.

    So TUDCA helps to protect the liver...and it also ameliorates endoplasmic reticulum stress. Funnily enough, ER stress is also implicated in pre-diabetes and metabolic syndrome which many of us experience along with MECFS. TUDCA helps to improve insulin sensitivity. Note also that calcium stores and channels are implicated yet again.

    The most commonly studied dosage of TUDCA for fatty liver disease is 1,750 mg/day. I've been taking it at 1,000 mg/day for a month or so. I'm planning to increase the dose to 1,500 mg soon. I've been buying it on Amazon.

    Here's a more scientific summary of ER stress (and a list of drugs known to trigger it):

    IrisRV likes this.
  2. Who Me?

    Who Me? Well-Known Member

    @Remy did it cure you?
  3. Remy

    Remy Administrator

    Surely by morning. ;)

    I took it slow though and have yet to ramp up to the final dosage that has been most studied.
    Who Me? likes this.
  4. Tina

    Tina Well-Known Member

    Stunning really. I never know what I am going to read about on this site. So much information. Until yesterday I had never heard of protein folding. I came across something with my own case that is leading me down a path regarding protein misfolding and then I see your post! Is that what you are talking about? protein misfolding?
  5. Remy

    Remy Administrator

    Yes! Same thing. Many names. :)
    Who Me? likes this.
  6. Who Me?

    Who Me? Well-Known Member

    Remy likes this.
  7. Who Me?

    Who Me? Well-Known Member
  8. Remy

    Remy Administrator

    It's probably a really good idea to buy it in bulk. It's kind of expensive when you get up in the higher doses otherwise.

    Yes, I think you've just got to try it and see. It probably isn't an overnight thing either as it would take time to correct damage.

    I didn't know that about the correcting visual problems, either. That's really interesting.
  9. Tina

    Tina Well-Known Member

    Not only the protein misfolding, but what I am looking at mentioned endothelium dysfuntion. I will post a lengthier response later as I am able to.
    Remy and IrisRV like this.
  10. Cort

    Cort Founder of Health Rising and Phoenix Rising Staff Member

    Thanks Remy! I had heard of ER stress but I had no idea what it is and was afraid it was going to be very complicated - but you explained it so well :)...

    Here's some more:

    Too many misfolded the proteins and the cell will kill itself. Interestingly it's a heat shock protein (hsp's - hsp's have been implicated in ME/CFS but not that one I don't think) - that keeps the protein from leaving the cell.

    Given all the exercise problems in ME/CFS it's interesting that exercise can disrupt ER functioning.

  11. Tina

    Tina Well-Known Member

    What I am going to add to this discussion is specific to my case, but hopefully may be a light bulb moment for others. I think many of us believe there is most likely not a single trigger for ME/CFS. More than likely it is some trigger that sets something in motion. I also suspect that it may have a genetic component as well. I am not sure that it will be one genetic thing or multiple. Just something that sets our bodies up to potentially react differently at some point.

    According to 23andme, I have the APOE4 gene, which puts me at a higher risk of getting Alzeheimer’s compared to the average and I have a gene that puts me at a higher risk of getting Type 2 Diabetes. I don’t have either.

    I am about to have neurocognitive testing done and in preparing for that, I am once again gathering all of my medical history. Something made me reach back, way back, to 2000. A full seven to eight years before my ME/CFS. In 2000, with my first live birth, I developed severe preeclampsia and acute kidney failure. At the time I was just told once I had the baby all danger was over. (In fact, I got the green light to get pregnant exactly 12 months later.) I am guessing that was the thinking at the time.

    However, when I looked at today’s literature on preeclampsia I was reading about misfolding protein, endothelium dysfunction, endoplasmic reticulum stress, Alzheimer’s and Type 2 Diabetes. And then one day later I see Remy’s post about ER stress and oxidative stress, both of which could explain PEM. I felt like I was looking at a nexus of my health issues.

    Here are a couple of articles:
    1. Understanding Pre-Eclampsia Using Alzheimer's Etiology: An Intriguing Viewpoint
    Amyloid precursor protein; autophagy; endoplasmic reticulum stress; pre-eclampsia; protein misfolding and aggregation disease; transthyretin

    2. Protein misfolding and aggregation in Alzheimer's disease and type 2 diabetes mellitus
    Remy likes this.
  12. Remy

    Remy Administrator

    I had to hunt a bit to find this, so I'll add it here.

    The SNPs involved in APOE are:

    rs7412 CC
    rs429358 TT

    So, I have average risk (the APOE3 version) because I have a C from the first SNP and a T from the second.

    @Tina has a T on both SNPs.
  13. Xandra

    Xandra New Member

    Hello, please could you tell me if you're still taking TUDCA and if it is helping? Did you get up to the maximum dose and what brand did you use?
    Thank you.
  14. DailySky

    DailySky New Member

    I tried TUDCA and got serious diarrhea. Many moons later I had an OAT that showed my pancreatic enzymes were low, so I upped them considerably, to create an overnight sensation! (good). Yay!

    I might try TUDCA again now that this seems to be under more control. Just a caution to those who have sensitive guts.... you might start slow on this first just in case...

    thanks for the post.