Unfolded Protein Response and A Possible Treatment for CFS

[Gondwanaland]

Why does he experience Ach surge?

I don't know... he's been avoiding eggs. At first I though it was due to sulfur, then due to choline, then due to protein. I don't know.

Why does B2 makes him depressed?

I think because it improves neurotransmitter breakdown and he is low in serotonin and dopamin.

Does he eat a lot of Protein (apart from the Whey Protein that he is taking)?

He doesn't tolerate whey, he took it once and got bedridden, then didn't take it anymore. Also all of a sudden he is eating like 80% carbs, I think because the high creatinine makes him feel poorly eating high protein like he used to eat most of the time (poor B12 recycling).

 

[mariovitali]

@Gondwanaland

I see. So let's assume that Whey got him bedridden because of too much Protein Ingestion and a subsequent Unfolded Protein Response (UPR).

If he's avoiding eggs, that means that he is not taking a major source of Choline (Choline insufficiency is a problem). Has he tried taking Choline Bitartate as a supplement?

Is it possible that he is deficient in serotonin/dopamine because of BH4 and/or GCH1 mutations? If he has them, then he has to stay away from Phenylalanine sources and Aspartame. Egg White is full of Phenylalanine :

Sources of Phenylalanine

He must also supplement with Dopa-Mucuna for boosting Dopamine and 5-HTP for serotonin.

And finally, has he tried taking TUDCA?

Sorry if i asked previously these questions !

 

[Ema]

Is it possible that he is deficient in serotonin/dopamine because of BH4 and/or GCH1 mutations? If he has them, then he has to stay away from Phenylalanine sources and Aspartame. Egg White is full of Phenylalanine :

I can't remember exactly but wasn't there some discussion a while ago about how phenylalanine could actually stimulate BH4? In that case, it wouldn't be necessary to avoid phenylalanine unless levels were already high, indicating some sort of PKU. It's possible to have low BH4 and associated neurotransmitter deficits without high phenylalanine too.

So it seems like phenylalanine supplementation (either with food or directly) could go both ways but for the majority of people with low BH4, it could actually be helpful to include phenylalanine rich foods in the diet.

 

[mariovitali]

I can't remember exactly but wasn't there some discussion a while ago about how phenylalanine could actually stimulate BH4? In that case, it wouldn't be necessary to avoid phenylalanine unless levels were already high, indicating some sort of PKU. It's possible to have low BH4 and associated neurotransmitter deficits without high phenylalanine too.

So it seems like phenylalanine supplementation (either with food or directly) could go both ways but for the majority of people with low BH4, it could actually be helpful to include phenylalanine rich foods in the diet.

This is not the case @Ema. Please see below :

Phenylketonuria
A deficit in tetrahydrobiopterin biosynthesis and/or regeneration can result in phenylketonuria (PKU) from excess L-phenylalanine concentrations or hyperphenylalaninemia (HPA), as well as monoamine and nitric oxide neurotransmitter deficiency or chemical imbalance. The chronic presence of PKU can result in severe brain damage, including symptoms of mental retardation, microcephaly, speech impediments such as stuttering, slurring, and lisps, seizures or convulsions, and behavioral abnormalities, among other effects.

Tetrahydrobiopterin, developed by BioMarin under the brand name Kuvan and approved by the United States (U.S.) Food and Drug Administration (FDA) on December 13, 2007 and European Medicines Agency (EMA) in 2008, is a synthetic preparation of the dihydrochloride salt of the substance containing ascorbic acid, used in the treatment of PKU and tetrahydrobiopterin deficiencies.[6] Sapropterin is the first non-dietary treatment for patients with PKU that has been shown in randomized, double-blind trials to be effective in lowering blood phenylalanine levels.[7]

So a BH4 deficiency leads always to high levels of Phenylalanine and high levels of Phenylalanine are not beneficial.

AFAIK, BH4 (Tetrahydrobiopterin) is boosted only by Kuvan, Vitamin C, Resveratrol and High-dose 5-MTHF supplementation and i haven't found any relevant references for Phenylalanine having this effect to Tetrahydrobiopterin (=increasing it).

 

[Gondwanaland]

If he's avoiding eggs, that means that he is not taking a major source of Choline (Choline insufficiency is a problem). Has he tried taking Choline Bitartate as a supplement?

He is taking it currently, but any supp seems to make him sleepy

He must also supplement with Dopa-Mucuna for boosting Dopamine and 5-HTP for serotonin.

He felt awful on Mucuna and I threw it away. I suspect he also has oxalate issues b/c 100mcg of K2-MK4 is unbearable and triggers his back pain

And finally, has he tried taking TUDCA?

We do not have access to it, but he is taking some Taurine.

We are not exposed to aspartame, but he is addicted to Coke, and seems to benefit from Phe as @Ema said. Coincidentally last night we agreed he would retry eating eggs at breakfast daily. I don't know what to tackle first, his high fasting insulin, high triglycerids, high creatinine, high homocysteine (he is taking P5P)...

Thanks for the nutrition list. We both have been enjoying watercress a lot lately and I didn't know it is high in Phe.

BH4 (Tetrahydrobiopterin) is boosted only by Kuvan, Vitamin C, Resveratrol and High-dose 5-MTHF

Also coincidentaly I will start him on a little vit C today (100mg only in case he is converting excess into oxalates).
Resveratrol - isn't it estrogenic? He has estrogenic fat at his waist.
Methylfolate made him very depressed
Folinic triggers his back pain

BH4 and/or GCH1 mutations

Please direct me to your previous post for me to check his 23andMe results. I probably checked it before but now I forget

 

[mariovitali]

@Gondwanaland

Please see here for more info regarding BH4, GCH1, etc


Did he try Mucuna Pruriens Raw Powder or an extract of Mucuna? What i meant to say is that he should supplement with Mucuna and 5-HTP if he has the GCH1 mutation and/or impaired BH4 synthesis. I also do not understand why he felt awful with Metafolin. Could you post his genetic genie report or send it over as a message?


Also recall that your SNPs (both yours and your husband's) suggested that you could be low in Choline. Again, i do not understand why Choline makes him sleepy (actually Taurine could be doing that). It should be the other way around! Something else is going on here...

To summarize, here is what i would do as an essential list :


Yes Resveratrol is indeed estrogenic. The only best way to lower E2 is to lose fat from his waist.



-Try avoiding all sources of Phenylalanine
-Try not eating too much meat
-Avoid too much sugar
-Supplement with 1 gram of Taurine per day
-Take Choline 350 - 500 mg per day
-Make sure you aren't/ he is not Gluten Intolerant

....It's a long essential list, i know

 

[Gondwanaland]

Please see here for more info regarding BH4, GCH1, etc

Have you never compiled a simple list of SNPs and risk allele? I just can't read all that info right now.

Did he try Mucuna Pruriens Raw Powder or an extract of Mucuna?

We only have access to regular Mucuna powder locally. I suppose it is raw.

Mucuna and 5-HTP

5-Htp helps him

Could you post his genetic genie report

His GG results are linked in my sig.

He feels so well eating gluten - unlike me. But I know it's the last thing he should be eating right now

 

[Ema]

This is not the case @Ema. Please see below :




So a BH4 deficiency leads always to high levels of Phenylalanine and high levels of Phenylalanine are not beneficial.

AFAIK, BH4 (Tetrahydrobiopterin) is boosted only by Kuvan, Vitamin C, Resveratrol and High-dose 5-MTHF supplementation and i haven't found any relevant references for Phenylalanine having this effect to Tetrahydrobiopterin (=increasing it).

This is unfortunately not true.

http://www.rainbow.coop/library/bio...e=detail&refno=980&submenu=NutritionalLibrary

 

[Ema]

his high fasting insulin

Apparently insulin resistance also lowers BH4...

 

[Ema]

Interesting article on BH4...

http://atvb.ahajournals.org/content/26/11/2439.full.pdf

Abstract—Tetrahydrobiopterin (BH4) is an essential cofactor for the aromatic amino acid hydroxylases, which are essential in the formation of neurotransmitters, and for nitric oxide synthase. It is presently used clinically to treat some forms of phenylketonuria (PKU) that can be ameliorated by BH4 supplementation. Recent evidence supports potential cardiovascular benefits from BH4 replacement for the treatment of hypertension, ischemia-reperfusion injury, and cardiac hypertrophy with chamber remodeling. Such disorders exhibit BH4 depletion because of its oxidation and/or reduced synthesis, which can result in functional uncoupling of nitric oxide synthase (NOS). Uncoupled NOS generates more oxygen free radicals and less nitric oxide, shifting the nitroso–redox balance and having adverse consequences on the cardiovascular system. While previously difficult to use as a treatment because of chemical instability and cost, newer methods to synthesize stable BH4 suggest its novel potential as a therapeutic agent. This review discusses the biochemistry, physiology, and evolving therapeutic potential of BH4 for cardiovascular disease. (Arterioscler Thromb Vasc Biol. 2006;26:2439-2444.)

 

[Violeta]

Again, sugar is a double-edged sword just like Calcium. I really appreciate your comments because it is valuable feedback so i can better express the regimen that i follow.

HmG-CoA is boosted by sugar and Cholesterol intake. However i didn't want to suggest that you should follow these steps.

Do you think adding B5 to the sugar and cholesterol formula (in moderation, of course) would be helpful?

 

[mariovitali]

@Gondwanaland

I will make the list in the next couple of days


@Violeta

I really do not know but you could try it and see how you feel


@Ema

The link you provided contains this :

Biopterin blood levels are a measure of BH4 in a person’s body and 80% of total biopterin appears in the blood as BH4. Plasma phenylalanine levels must be tested at the same time as blood tests are done for BH4 because phenylalanine increases BH4 levels.

However what i feel is happening here is that a person called "Dr Pack" is using the paper named

"Analysis of Plasma Biopterin Levels in Psychiatric Disorders Suggests a Common BH4 Deficit in Schizophrenia and Schizoaffective Disorder."

and is making an incorrect -actually dangerous- statement that Phenylalanine supplementation increases BH4. I still cannot find any reference on the link you provided or PubMed entry that Phenylalanine increases BH4. If possible please provide a link directly from Pubmed that clearly states that Phenylalanine increases BH4.

Not only this statement is false, it could have serious -even fatal- consequences to people that have PKU.

 

[Ema]

Not only this statement is false, it could have serious -even fatal- consequences to people that have PKU.

But that's the point...if you *don't* have PKU, phenylalanine increases BH4.

And since most people don't have PKU (and would know it if they did fairly early on in life), that makes supplementing phenylalanine a reasonable and inexpensive first step for boosting BH4 levels.

Pg 266 in Advances in Human Genetics, Vol 13 also states:

"This last observation also indicated that phenylalanine was stimulating BH4 synthesis by stimulating the first step in the pathway"

 

[mariovitali]

But that's the point...if you *don't* have PKU, phenylalanine increases BH4.

And since most people don't have PKU (and would know it if they did fairly early on in life), that makes supplementing phenylalanine a reasonable and inexpensive first step for boosting BH4 levels.

Pg 266 in Advances in Human Genetics, Vol 13 also states:

"This last observation also indicated that phenylalanine was stimulating BH4 synthesis by stimulating the first step in the pathway"

OK, it appears that this is the case, *but* you might have impaired BH4 recycling (as i have, due to an MTHFR Mutation) and a GCH1 mutation (which i also have) and thus not full-blown PKU, just impaired BH4 Production and recycling (aka non-PKU Hyperphenylalaninemia or BH4 deficiency). I felt really bad when i was taking Aspartame and eating too many Phenylalanine-rich foods. My initial "crash" in CFS happened when i ate a lot of Egg whites because i was at a strict diet at that time and wanted to eat no-fat protein.

Many people here take Kuvan because of impaired BH4 recycling and/or a GCH1 Mutation . I believe that if they try to supplement with Phenylalanine they *will* feel much worse.

Vitamin C has greatly helped me and i believe this happens because it recycles BH4 production. The same applies (=BH4 recycling) for the large dose of Metafolin i am taking (2000 mcg)

 

[Violeta]

Unfolded/misfolded proteins and autoinflammatory diseases. Sorry, don't have entire article.

http://www.nature.com/nri/journal/v12/n8/glossary/nri3261.html

 

[Violeta]

And with relation to dopaminergic neurons. (restless leg syndrome for example)

http://www.ncbi.nlm.nih.gov/pubmed/18313225

 

[mariovitali]

@Violeta

Please have a look here for a possible connection between Misfolded Proteins, the Unfolded Protein Response and Inflammation

 

[Violeta]

@Violeta

Please have a look here for a possible connection between Misfolded Proteins, the Unfolded Protein Response and Inflammation

So this is a very overlooked side of inflammation. I don't understand exactly what those studies mean yet, but I can see the bottom line.

Do you mind if I ask what the "glucose" part of this means with respect to glucose in the diet, does glucose help or hurt the process? etc, you can tell I don't even know the right way to ask the question.
glucose-regulated ER stress protein (grp)-78

 

[mariovitali]

So this is a very overlooked side of inflammation. I don't understand exactly what those studies mean yet, but I can see the bottom line.

Do you mind if I ask what the "glucose" part of this means with respect to glucose in the diet, does glucose help or hurt the process? etc, you can tell I don't even know the right way to ask the question.
glucose-regulated ER stress protein (grp)-78

Glucose induces the expression of Grp78 (which generally is a good thing with Grp-78 being a chaperone) but in the same time elevated glucose may have detrimental effects if someone has Glucose Intolerance (GI creates ER Stress).

 

[aquariusgirl]

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