ER Stress, Protein Misfolding, TUDCA.

[Remy]

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):

Definition and Cellular Consequences of ER Stress

The ER plays a crucial role in the synthesis of all the proteins that are secreted from cells, or inserted into organelle membranes. Efficient protein folding in the ER requires a tight coupling between the arrival of new proteins in the ER lumen and the ER folding capacity. Efficient folding requires ER‐resident proteins such as chaperones and foldases that are calcium‐binding/buffering proteins (Coe and Michalak 2009; Halperin et al. 2014). These proteins include for instance calreticulin, glucose‐regulated protein 78 (GRP78, also known as immunoglobulin‐binding protein or BiP), GRP94, and protein disulfide isomerase (PDI).

When the demand for protein folding increases (e.g., enhanced protein synthesis, accumulation of mutated, or abnormal proteins, etc) and exceeds protein folding capacity, misfolded/unfolded proteins accumulate in the ER lumen and trigger an ER stress.

Many physiological or pathological situations can interfere with protein folding and can thus impact ER homeostasis such as alterations of ER luminal calcium stores, energy depletion, redox disturbances, glucose starvation, lipid accumulation, viruses, ethanol intoxication, and xenobiotics (Malhi and Kaufman 2011; Cnop et al. 2012; Cheng et al. 2013; Chen et al. 2014).

Notably, ER stress is leading to the activation of the so‐called unfolded protein response (UPR), the role of which is to maintain protein homeostasis by decreasing the load of unfolded proteins and increasing the protein folding capacity (Fig. 1).

In addition, ER stress is also able to activate autophagy‐ and proteasome‐dependent proteolysis when misfolded proteins are in excess (Hoyer‐Hansen and Jäättelä 2007; Digaleh et al. 2013).

 

[Who Me?]

@Remy did it cure you?

 

[Remy]

@Remy did it cure you?

Surely by morning.

I took it slow though and have yet to ramp up to the final dosage that has been most studied.

 

[Tina]

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?

 

[Remy]

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?

Yes! Same thing. Many names.

 

[Who Me?]

For those interested in bulk I found this. Powder City is reliable.

http://www.powdercity.com/products/tudca-tauroursodeoxycholic-acid

@Remy So is TUDCA one of those things you try and see if it helps?

 

[Who Me?]

1. TUDCA helps to protect our liver. Believe it or not, TUDCA is more effective than milk thistle. TUDCA may even reverse liver disease. In addition, TUDCA has the ability to remove poisonous chemicals in the bile protecting the liver from any poisoning and diseases caused by toxic materials.

2. TUDCA also helps to control cholesterol levels in the liver. TUDCA helps in protecting humans from cholestasis because it has the ability to break down fats resulting to a healthy liver. In addition, it also protects the nerves so that the nerves in the liver will not die due to other infections. This also suggests that TUDCA is a cholesterol fighter. In addition, TUDCA is also used to treat gallstones with high level of cholesterol.

3. TUDCA is also helpful in weight loss so it is beneficial to people with fatty liver or people who want to lose fat in their bodies. TUDCA has the ability to burn fats and TUDCA is also a cholesterol fighter.

4. TUDCA is also used in other medications to treat visual disorders. A lot of visual disorders are prevented because of the application of TUDCA and other bile acid supplements such as taurine. TUDCA is also known for the treatment of retinitis pigmentosa, a disease where retinal rods experiences apoptosis or programmed cell death. These suggest that TUDCA really plays an important role in the treatment and prevention of visual disorders and diseases.

5. TUDCA protects nerve cells from death. As I have mentioned earlier, TUDCA fights with the toxic materials in the liver making the liver healthy and free from cholesterol. By this action, TUDCA is indirectly protecting the cells because as TUDCA fights toxic materials in the body, there will be no toxic elements that kill the nerves. In addition, TUDCA also reduces the stress that nerves experience making it a promising neuro protecting agent.

6. TUDCA may also aid in the treatment of Huntington’s disease. What makes it as a promising agent to treat this disease? TUDCA is water soluble which means it can pass through the blood brain barriers making it easier to deliver medications into the different parts of the body. In addition, it doesn’t give any side effects because it is naturally produced in the body and it protects nerve cells from death. Because of these characteristic, it may also be a promising treatment for Parkinson’s disease and other diseases related to such.

7. As I have mentioned earlier in our discussion, TUDCA is also considered as a neuro protective agent, thus people who experienced stroke may as well benefit from TUDCA supplements. TUDCA protects the nerves, this means that a person may experience lesser or decreased damage on his/her nerves concerning the brain.

8. People who are drinking may also benefit from TUDCA because tauroursodeoxycholic acid may also protect the liver from damages due to alcohol. However, TUDCA should be taken after drinking alcohol because TUDCA may be damaging to the liver when it is taken before drinking alcohol.

The Side Effects Of TUDCA
Provided above are the different benefits of tauroursodeoxycholic acid when it is taken inside a human body. However, does TUDCA give any side effects? Is TUDCA generally safe to users who want to protect their liver as well as their nerve cells? TUDCA is generally safe for its users as long as it is taken with care and caution. There are no listed side effects of TUDCA because as I have mentioned earlier, it is naturally produced in the body and it plays a key role in protecting the liver as well as digesting and absorbing essential vitamins and minerals that are needed by the body.

Why You Should Buy TUDCA?
TUDCA supplements are compounds that may help you improve your lifestyle. If you think that you are in need of TUDCA supplements, what are you waiting for, buy TUDCA supplements now and harvest its effects. Where can you buy TUDCA supplements? You can buy them in drugstores because it is sold as a supplement and you can also buy TUDCA supplements online. TUDCA is a promising supplement but if you are not sure whether you can take it or not especially when you are under medication, you should ask your physician first to ensure safety and to avoid negative results. In addition, best effects of TUDCA are experienced as long as it is taken with discipline and caution.

https://www.linkedin.com/pulse/8-reasons-everyone-should-take-tudca-ryan-williams

 

[Remy]

For those interested in bulk I found this. Powder City is reliable.

http://www.powdercity.com/products/tudca-tauroursodeoxycholic-acid

@Remy So is TUDCA one of those things you try and see if it helps?

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.

 

[Tina]

Yes! Same thing. Many names.

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.

 

[Cort]

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:

Sustained overactivation of the UPR has been implicated in prion diseases as well as several other neurodegenerative diseases, and inhibiting the UPR could become a treatment for those diseases.[2] Diseases amenable to UPR inhibition include Creutzfeldt-Jakob disease, Alzheimer's disease, Parkinson's disease, and Huntington's disease.[3

]

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.

Skeletal muscles are sensitive to physiological stress, as exercise can impair ER homeostasis. This causes the expression of ER chaperones to be induced by the UPR in response to the exercise-induced ER stress. Muscular contraction during exercise causes calcium to be released from the sarcoplasmic reticulum (SR), a specialized ER network in skeletal muscles. This calcium then interacts with calcineurin and calcium/calmodulin-dependent kinases that in turn activate transcription factors. These transcription factors then proceed to alter the expression of exercise-regulated muscle genes. PGC-1alpha, a transcriptional coactivator, is a key transcription factor involved in mediating the UPR in a tissue-specific manner in skeletal muscles by coactivating ATF6alpha. Therefore, PGC-1alpha gets expressed in muscles after acute and long-term exercise training. The function of this transcription factor is to increase the number and function of mitochondria, as well as to induce a switch of skeletal fibers to slow oxidative muscle fibers, as these are fatigue-resistant. Therefore, this UPR pathway mediates changes in muscles that have undergone endurance training by making them more resistant to fatigue and protecting them from future stress.[8]

 

[Tina]

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
Keywords: Amyloid precursor protein; autophagy; endoplasmic reticulum stress; pre-eclampsia; protein misfolding and aggregation disease; transthyretin
http://onlinelibrary.wiley.com/doi/...enticated=false&deniedAccessCustomisedMessage=

2. Protein misfolding and aggregation in Alzheimer's disease and type 2 diabetes mellitus
http://www.ncbi.nlm.nih.gov/pubmed/25230234

 

[Remy]

I have the APOE4 gene

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.

 

[Xandra]

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.

 

[DailySky]

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.

 

[Nicolaas]

I read somewhere to only expect results from Tudca after 6 months. I started taking tudca and after 8 months of use I was still only experiencing improvement in my liver function: THEN I started following the advice to also take 1000 microgram of vitamin B12 daily. That combination works very well. I now have more energy, allergies are improving, better mental clarity and I am more productive.

 

[Nicolaas]

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.

I am taking 250 mg, three times per day. (One capsule every 8 hours) Brand: Since I am in South Africa, I use the South African brand, "Neuroactive".