Unfolded Protein Response and A Possible Treatment for CFS

mariovitali · Jul 17, 2015

I would try TUDCA at 750 mg per day

Violeta · Jul 17, 2015

It is starting to seem as though I could google endoplasmic reticulum along with any condition and find some sort of link.

This article shows that there are autoantibodies to some of the protein chaperones to the ER in autoimmune diseases RA and Lupus. Summary says that pathogens were not responsible for the autoantibodies.
http://www.ncbi.nlm.nih.gov/pubmed/20716673

Then you see in this study that those chaperones are responsible for degrading misfolded proteins. http://jcb.rupress.org/content/165/1/41.abstract

JPV · Jul 17, 2015

Violeta said:

I think the big question is whether some sort of toxins and/or infections are causing the ER Stress or is there some sort of genetic defect in the ER.

Violeta · Jul 18, 2015

After seeing that someone with polymyositis came down with it after taking statins (and so did his mother), I thought I would see if it involved endoplasmic reticulum stress, and sure enough.

http://www.ncbi.nlm.nih.gov/pubmed/21191666

Epstein Barr Virus is involved in polymyositis, too, just for the record.

http://www.hindawi.com/journals/jir/2013/535738/

Violeta · Jul 18, 2015

JPV said:

This article has a lot of information about it.

http://www.jci.org/articles/view/26373

Violeta · Jul 18, 2015

From a biology 1 page:
"You need to be able to use your knowledge of the structure of cells and the function of the organelles to interpret electronmicrographs of cells. In particular the epithelial cells lining the small intestine. These are cells which are specialised for absorbing the products of digestion. They will therefore have a large surface area provided by the microvilli and due to the need for active transport across their cell membranes they will contain a large number of mitochondria providing them with ATP. Epithelial cells also secrete enzymes and other proteins. This means that they will have a large and visible endoplasmic reticulum, Golgi apparatus to allow protein production and secretion."

And I didn't realize this, but there are two types, and I suppose some could have issues more in the intestines and some more likely to have issues in the liver.

"Endoplasmic Reticulum (ER)

Rough ER
- Have ribosomes attached to the cytosolic side of their membrane
- Found in cells that are making proteins for export (enzymes, hormones, structural proteins, antibodies)
- Thus, involved in protein synthesis
- Modifies proteins by the addition of carbohydrates, removal of signal sequences
- Phospholipid synthesis and assembly of polypeptides
Smooth ER
- Have no ribosomes attached and often appear more tubular than the rough ER
- Necessary for steroid synthesis, metabolism and detoxification, lipid synthesis
- Numerous in the liver

Viral proteins, seems to be a common thread.

http://www.ncbi.nlm.nih.gov/pubmed/23293645

mariovitali · Jul 19, 2015

Lots of goodies Ladies and Gentlemen

A first run was completed from my software and here are the topics most commonly matched :

So ER Stress and TUDCA matches the concepts more frequently ( i will explain in another post). Notice that something called XBP1 is mentioned. So this among other things works for :

Upon further reading i ended up with these genes which play important role in ER Stress and UPR Sensing and Handling (Credit to @Violeta)

rs13045 (EIF2AK3-PERK) : Risk C : (C;C)
rs2239815(XBP1) : Risk C (T;T)
rs10918270(ATF6) : Risk A (A;G)
rs391957 (HSPA5) : Risk C (C;T)

Could you please have a look at your SNPs for these genes and let us know?

JPV · Jul 19, 2015

mariovitali said:

rs13045 : Doesn't show up on my 23andMe report.
rs2239815 : CT
rs10918270 : AG

mariovitali · Jul 19, 2015

JPV said:

So you have two heterozygous mutations in rs2239815 and rs10918270.

This probably means that despite what happens with rs13045, you have impaired ER Protein Folding sensing capacity and as a result ER Stress and UPR.

If you also have impaired Choline absorption and Methylation mutations, that means that things are getting very difficult for you when it comes to ER Stress and Misfolded Protein control.

EDIT : Please look also at

rs391957 (HSPA5) : Risk C (Mine is C;T)

mariovitali · Jul 19, 2015

@Violeta, @JPV, @Gondwanaland

To recap, please check the following Gene SNPs (in bold i have Genes with SNPs that i found for me):

ER Stress response

rs13045 (EIF2AK3-PERK) : Risk C
rs2239815(XBP1) : Risk C
rs10918270(ATF6) : Risk A
rs391957 (HSPA5 aka BIP aka GPR78) : Risk C

GCH1, associated with lower levels of BH4 (low BH4 => ER Stress)

rs10483639 : ( Risk C)
rs3783641 : (Risk A)
rs8007267 : (Risk T)
rs12147422 : (Risk C)
rs3783637 : (Risk T)
rs3783641 : (Risk A)
rs41298442 : (Risk T)
rs4411417 : (Risk C)
rs752688 : (Risk T)
rs841 : (Risk A)
rs998259 : (Risk T)
rs7147286 : (Risk A)

Choline Metabolism (impaired Choline absorption => impaired TMAO => ER Stress+UPR)

rs3733890 (Risk A)
rs2461823 (Risk C) NAFLD Disease
Rs7643645 Risk G NAFLD Disease
rs7946 (Risk T) (PEMT)
rs4244593 (Risk G) (associated with PEMT)
rs2236225 (Risk A) (MTHFD1) -
rs9001 (Risk G) (CHDH)

Violeta · Jul 19, 2015

This is something I've been seeing in studies about ER stress that surprised me. I have to find a site where I can get the whole article. Caffeine induced calcium release!

"

y A VERKHRATSKY - ‎2004 - ‎Cited by 45 - ‎Related articles
Endoplasmic reticulum calcium signaling in nerve cells ... Disruption of ER Ca2+homeostasis triggers several forms of cellular stress response and is .... Within the next decade, this caffeine-induced Ca2+ release was found in many types of ..."

Violeta · Jul 19, 2015

I was just wondering if ER stress causes glucose intolerance instead of the the other way around and found this. I don't know the anwer to that yet, but this is interesting.

http://onlinelibrary.wiley.com/doi/10.1038/oby.2008.217/pdf

Violeta · Jul 19, 2015

mariovitali said:

I have never had genetic testing done. But I do find it interesting. I see the choline metabolism genes are related to NAFLD, and I do believe I had that as choline made the biggest difference in my condition.

I do also wonder how much of a part NAFLD has in causing genetic issues. Perhaps it's a vicious circle.

leela · Jul 19, 2015

rs2239815(XBP1) : Risk C (T;T) CC
rs10918270(ATF6) : Risk A (A;G) AG
rs391957 (HSPA5) : Risk C (C;T) CT

Rs7643645 Risk G GG

mariovitali · Jul 19, 2015

@Violeta

I think that the main problem with me is Liver function. My nephew was born with some sort of Biliary Atresia, a form of Cholestasis. I don't think that this happened by chance. The doctors had to contact a very specialized Medical center in London and to send over sample from his liver to identify whether it was atresia or not.

The doctors asked from my sister and her husband to take DNA tests which hasn't happened so we don't really know why this incident happened.

I would kindly advise you to have a DNA test ASAP so you know exactly what is going on. If you ask me regarding my choice to take a DNA test, i believe these were the most well-spent $99 i gave.

SDSue · Jul 19, 2015

Hi @mariovitali. I’m new to this thread, but hopeful that you might still be able to look at my SNPs. It seems our GCH1’s are identical. Thanks so much!

ER Stress response

CC rs13045 (EIF2AK3-PERK) : Risk C
CT rs2239815(XBP1) : Risk C
GG rs10918270(ATF6) : Risk A
TT rs391957 (HSPA5 aka BIP aka GPR78) : Risk C

GCH1, associated with lower levels of BH4 (low BH4 => ER Stress)

CG rs10483639 : ( Risk C)
AT rs3783641 : (Risk A)
CT rs8007267 : (Risk T)
TT rs12147422 : (Risk C)
CC rs3783637 : (Risk T)
AT rs3783641 : (Risk A)
TT rs41298442 : (Risk T)
CT rs4411417 : (Risk C)
CT rs752688 : (Risk T)
AG rs841 : (Risk A)
CC rs998259 : (Risk T)
AG rs7147286: (Risk A)

Choline Metabolism (impaired Choline absorption => impaired TMAO => ER Stress+UPR)

GG rs3733890 (Risk A)
TT rs2461823 (Risk C) NAFLD Disease
AG Rs7643645 Risk G NAFLD Disease
TT rs7946 (Risk T) (PEMT)
TT rs4244593 (Risk G) (associated with PEMT)
GG rs2236225 (Risk A) (MTHFD1) -
TT rs9001 (Risk G) (CHDH)

mariovitali · Jul 19, 2015

@leela

You have impaired ER Stress /Misfolded protein sensing due to your 3 SNPs to XBP1,ATF6,HSPA5

The homozygous mutation you have for rs7643645 means that you could be deficient in Choline.

@SDSue

You have mutations in ER Stress response genes, GCH1 and Choline metabolism so you could try the regimen explained in this thread.

@leela, @SDSue

What about SNPs to methylation genes? (MTHFR,CBS etc)

Gondwanaland · Jul 19, 2015

Thank you so much for the lists, @mariovitali

Here are my results, followed by my husband's

ER Stress response

rs13045 (EIF2AK3-PERK) : Risk C No SNPs matching 'rs13045' found in the data from your chip.
rs2239815(XBP1) : Risk C TT/CT
rs10918270(ATF6) : Risk A GG/AG
rs391957 (HSPA5 aka BIP aka GPR78) : Risk C No SNPs matching 'rs391957' found in the data from your chip.

GCH1, associated with lower levels of BH4 (low BH4 => ER Stress)

rs10483639 : ( Risk C) GG/GG
rs3783641 : (Risk A) TT/TT
rs8007267 : (Risk T) CC/CC
rs12147422 : (Risk C) TT/CT
rs3783637 : (Risk T) CC/CT
rs3783641 : (Risk A) TT/TT
rs41298442 : (Risk T) TT/TT
rs4411417 : (Risk C) TT/TT
rs752688 : (Risk T) CC/CC
rs841 : (Risk A) No SNPs matching 'rs841' found in the data from your chip.
rs998259 : (Risk T) CT/CT
rs7147286 : (Risk A) GG/AG

Choline Metabolism (impaired Choline absorption => impaired TMAO => ER Stress+UPR)

rs3733890 (Risk A) GG/GG
rs2461823 (Risk C) NAFLD Disease TT/CC
Rs7643645 Risk G NAFLD Disease TT/CC
rs7946 (Risk T) (PEMT) TT/CT
rs4244593 (Risk G) (associated with PEMT) GG/GG
rs2236225 (Risk A) (MTHFD1) GG/AA
rs9001 (Risk G) (CHDH) GT/TT

leela · Jul 19, 2015

@mariovitali, thanks for posting about all this. so much to learn always!
my methylation/detox SNPs are :

+/-
COMT V158M, COMT H62H, MAO A, MTHFR C677T, MTHFR A1298C, MTR A2756G, MTRR A664A, BHMT-08, CBS C699T

+/+
VDR Taq, MTRR A66G, BHMT-02, BHMT-04

As you can see my BHMT pathways are fairly well hosed.

ETA: and I also have mild PKU.

mariovitali · Jul 19, 2015

@Gondwanaland

Luckily it appears that you have no problems in ER Stress signalling / handling although we cannot be certain since some Genes are not included in your chip's data. DH has some SNPs in ER Stress handling (and possibly more).

You both have problems with both Choline and GCH1 (homozygous mutations), so i believe you should supplement with Choline and high doses of Metafolin and Vitamin C. IMHO you should try supplementing with Choline but without taking Clostridium Butyricum since it lowers TMAO.

If you are afraid for the consequences of TMAO (being atherogenic) you could try for a week taking 700 mg of Choline and seeing how you both feel.

@leela

You said you have mild PKU, do you know which SNPs you have?

I am assuming that you are taking Methylation supplements (Metafolin, B12, P5P, etc) perhaps it would help you to start supplementing with TUDCA, not eating too much protein (which i believe you must be doing already)

You could also try supplementing with Choline, up to 700 mg per day to see how you feel but without taking any CB/Miyarisan to boost butyrate.

Unfolded Protein Response and A Possible Treatment for CFS

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