Unfolded Protein Response and A Possible Treatment for CFS

[mariovitali]

I have the Mthfr & GCH1 but can't tolerate BH4...makes me detox like crazy

I would try TUDCA at 750 mg per day

 

[Violeta]

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]

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

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]

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]

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.

This article has a lot of information about it.

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

 

[Violeta]

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]

Lots of goodies Ladies and Gentlemen


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

=============================File Statistics===============================================
er_stress.csv : 24
tudca.csv : 22
upr.csv : 22
xbp1.csv : 21
tetrahydrobiopterin.csv : 21
sirt1.csv : 20
gtp_cyclohydrolase.csv : 20
excitotoxicity.csv : 20
resveratrol.csv : 20
mitochondrial_dysfunction.csv : 19
oxidative_stress_markers.csv : 19
oxidative_stress_protection.csv : 19
ros.csv : 18
pgc1.csv : 18
ire1.csv : 18
cyp2e1.csv : 18
o-glcnac.csv : 18
steroidogenesis_human.csv : 17
endothelial_nos.csv : 17
pxr.csv : 17
zinc_supplementation.csv : 17
srd5a3.csv : 17
p450scc.csv : 16
caspase_human.csv : 16
cyp3a4.csv : 16
star.csv : 16
5mthf.csv : 15
hydroxysteroid_dehydrogenase.csv : 15
cyp1a2.csv : 15
car.csv : 15
cortisol_levels.csv : 15
nadph_human.csv : 15
mcp-1.csv : 14
peroxynitrite.csv : 14

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 :

Viral replication[edit]
This protein has also been identified as a cellular transcription factor that binds to an enhancer in the promoter of the T cell leukemia virus type 1 promoter. The generation of XBP-1s during plasma cell differentiation also seems to be the cue for Kaposi's sarcoma-associated herpesvirusand Epstein Barr virus reactivation from latency.

Endoplasmic reticulum stress response[edit]
XBP-1 is part of the endoplasmic reticulum (ER) stress response, the unfolded protein response (UPR).[6] Conditions that exceed capacity of the ER provoke ER stress and trigger the unfolded protein response (UPR). As a result GRP78 is released from IRE1 to support protein folding.[8]IRE1 oligomerises and activates its ribonuclease domain through auto (self) phosphorylation. Activated IRE1 catalyses the excision of a 26 nucleotide unconventional intron from ubiquitously expressed XBP-1u mRNA, in a manner mechanistically similar to pre-tRNA splicing. Removal of this intron causes a frame shift in the XBP-1 coding sequence resulting in the translation of a 376 amino acid, 54 kDa, XBP-1s isoform rather than the 261 amino acid, 33 kDa, XBP-1u isoform. Moreover the XBP-1u/XBP-1s ratio (XBP-1-unspliced/xbp-1-spliced ratio) correlates with the expression level of expressed proteins in order to adapt the folding capacity of the ER to the respective requirements.[9]

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]

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

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

 

[mariovitali]

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

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]

@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]

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]

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]

@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)

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]

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]

@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]

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]

@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]

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]

@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]

@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.