ME/CFS/LongCOVID Hypothesis: Three Subtypes of Noradrenergic Neuron Dysfunction

[datadragon]

BH4 by the way is necessary for the conversion of phenylalanine to tyrosine by PAH, tyrosine to L-DOPA by tyrosine hydroxylase (TH) leading to the production of dopamine and norepinephrine and and tryptophan to 5-HTP leading to the production of serotonin.

Here we show that in Vitamin D VDR-expressing SH-SY5Y cells, the active form of Vitamin D 1,25(OH)2D3 significantly increased production of tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine synthesis. https://www.sciencedirect.com/science/article/abs/pii/S0306452215006624

Zinc interestingly I found was involved there as well. The vitamin D receptor (VDR) binds zinc, and the activity of vitamin D dependent genes in cells is influenced by intracellular zinc concentrations. So again taking Vitamin D, the VDR functions of Vitamin D may be impacted with a zinc deficiency during chronic inflammation/infection states. https://forums.phoenixrising.me/threads/dang-those-vitamin-d3-levels.91152/page-2#post-2450071

Butyrate, a gut-derived environmental signal, regulates tyrosine hydroxylase gene expression via a novel promoter element https://pubmed.ncbi.nlm.nih.gov/16165221/ Butyrate levels also were shown to be lowered via a zinc deficiency state in animal studies. Increased propionic acid production and a corresponding reduction in butyric acid were also associated with zinc deficiency in young lambs as one example. https://www.sciencedirect.com/science/article/abs/pii/S002231662314346X?via=ihub

Butyrate increases the enzyme that produces dopamine (tyrosine hydroxylase) which converts L-tyrosine to L-dopa. The known ability of propionate (shared with butyrate) to promote dopamine and norepinephrine synthesis by enhancing the transcription of the tyrosine hydroxylase gene may be the mechanism underlying these molecular and behavioral effects. https://pubmed.ncbi.nlm.nih.gov/16165221/
https://www.sciencedirect.com/science/article/abs/pii/S0006899306032719

So numerous pathways can all be affected all at once with the switch to an inflammatory state like a see-saw. Many HDACs that butyrate relies on are zinc-dependent enzymes which require the zinc ion for the catalytic reaction. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6009916/

 

[Violeta]

BH4 by the way is necessary for the conversion of phenylalanine to tyrosine by PAH, tyrosine to L-DOPA by tyrosine hydroxylase (TH) leading to the production of dopamine and norepinephrine and and tryptophan to 5-HTP leading to the production of serotonin.

Here we show that in Vitamin D VDR-expressing SH-SY5Y cells, the active form of Vitamin D 1,25(OH)2D3 significantly increased production of tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine synthesis. https://www.sciencedirect.com/science/article/abs/pii/S0306452215006624

Zinc interestingly I found was involved there as well. The vitamin D receptor (VDR) binds zinc, and the activity of vitamin D dependent genes in cells is influenced by intracellular zinc concentrations. So again taking Vitamin D, the VDR functions of Vitamin D may be impacted with a zinc deficiency during chronic inflammation/infection states. https://forums.phoenixrising.me/threads/dang-those-vitamin-d3-levels.91152/page-2#post-2450071

Butyrate, a gut-derived environmental signal, regulates tyrosine hydroxylase gene expression via a novel promoter element https://pubmed.ncbi.nlm.nih.gov/16165221/ Butyrate levels also were shown to be lowered via a zinc deficiency state in animal studies. Increased propionic acid production and a corresponding reduction in butyric acid were also associated with zinc deficiency in young lambs as one example. https://www.sciencedirect.com/science/article/abs/pii/S002231662314346X?via=ihub

Butyrate increases the enzyme that produces dopamine (tyrosine hydroxylase) which converts L-tyrosine to L-dopa. The known ability of propionate (shared with butyrate) to promote dopamine and norepinephrine synthesis by enhancing the transcription of the tyrosine hydroxylase gene may be the mechanism underlying these molecular and behavioral effects. https://pubmed.ncbi.nlm.nih.gov/16165221/
https://www.sciencedirect.com/science/article/abs/pii/S0006899306032719

So numerous pathways can all be affected all at once with the switch to an inflammatory state like a see-saw. Many HDACs that butyrate relies on are zinc-dependent enzymes which require the zinc ion for the catalytic reaction. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6009916/

That's interesting. I was just wondering while being awake in the middle of the night what could possibly cause someone to be low in a number of neurotransmitters.

It's interesting, too, because studies have shown that people with ME/CFS tend to have lower levels of butyrate, and Standford is looking for people with ME/CFS to participate in a study about BH4.

I am seeing studies saying people with ME/CFS tend to have higher levels of BH4 in their blood than controls. This is said to cause higher than appropriate levels of nitric oxide. I'm going to have to look into that.

@Nord Wolf, did you see this?

 

[Violeta]

I am seeing studies saying people with ME/CFS tend to have higher levels of BH4 in their blood than controls. This is said to cause higher than appropriate levels of nitric oxide. I'm going to have to look into that.

This is the probable reason for higher than normal levels of BH4 in people with ME/CFS.

This is from a study by Dr. Avik Roy, who won a Solve Ramsay Research Grant to develop new models for studying ME/CFS. Dr. Roy and his team have now published a paper in the Journal of Central Nervous System Disease that explains why some patients with ME/CFS experience orthostatic imbalance (sharply decreased blood pressure when they stand), which can cause dizziness, lightheadedness, or even fainting. Characteristically, Dr. Roy’s inventive team created an interesting new experimental model for this study, which they used to dissect the metabolic missteps responsible for this effect.


"In the pentose phosphate pathway, a six-carbon sugar (glucose) is broken down into a five-carbon sugar (ribose 5-phosphate; hence the name, pentose) and NADPH. Like tetrahydrobiopterin, NADPH is a critical cofactor; for example, one of NADPH’s important jobs is to protect against dangerous oxygen species, like free radicals. If cells need lots of NADPH (for example, if oxygen levels are high), then the cells can recycle the five-carbon sugar back into the six-carbon one to keep making NADPH. But if cells need little NADPH (for example, if oxygen levels are low), then they can instead use the five-carbon sugar to make other important molecules, like tetrahydrobiopterin.

Dr. Roy’s team found that the pentose phosphate pathway was more active in patients than it was in healthy participants, and the levels of other enzymes needed to convert the five-carbon sugar into tetrahydrobiopterin were higher as well. Patients with ME/CFS often have respiratory problems that lower oxygen levels in tissues, explaining why the pentose phosphate pathway produced more tetrahydrobiopterin (instead of NADPH) in these patients.

 

[sb4]

If NET is reduced then norepinephrine just sits in the synapse meaning it doesn't get broken down in the cell as much and doesn't get produced as much (as the post synapse is already getting stimulated with enough norepinephrine). This is why my VMA (a breakdown product of norepinephrine) is low, yet my HVA (breakdown of dopamine) is normal (dopamine extracellular transporters are working).

The author of the paper messaged me to say that VMA cant be used to measure norepinephrine break down in the cell as it is produced extracellularly as well.

 

[datadragon]

It's interesting, too, because studies have shown that people with ME/CFS tend to have lower levels of butyrate, and Standford is looking for people with ME/CFS to participate in a study about BH4.

I am seeing studies saying people with ME/CFS tend to have higher levels of BH4 in their blood than controls. This is said to cause higher than appropriate levels of nitric oxide. I'm going to have to look into that.

Normally inflammation at first under conditions of oxidative stress, BH4 availability is diminished due to its oxidation, which subsequently leads to NOS uncoupling and generation instead of INOS and highly oxidative free radicals including superoxide and peroxynitrite. This is mainly due to the reduced uptake and availability of zinc during inflammation/infection states since its involved in BH4 synthesis pathways as well as INOS switching (see below).

However then, GCH1, which is normally the rate-limiting enzyme for BH4 synthesis, is increased up to 100-fold by interferon-gamma (IFN-y) or IL-1B (usually in response to a pathogen). At this point, the other enzymes in the biosynthetic pathway become the rate-limiting factors https://pmc.ncbi.nlm.nih.gov/articles/PMC8573752/ Perhaps this is to help boost INOS for a short time to deal with an invader/pathogen as well as histamine and serotonin release as below.

Researchers have found that overexpression of GCH1, which drives higher BH4 production, causes increased histamine and serotonin release from mast cell degranulation. Mast cells are a part of the innate immune response. They can respond rapidly to allergens and pathogens by degranulating and releasing histamine, serotonin, cytokines, and more. https://pubmed.ncbi.nlm.nih.gov/3045083/

Also again, things like infection, heavy exercise and even high glucose or fructose all increase IFN-y. Elevated BH4 levels could be a natural response to elevated ifn-y in a reactivated Epstein-Barr infection as but one example.
https://pubmed.ncbi.nlm.nih.gov/21448390/
https://pubmed.ncbi.nlm.nih.gov/34867935/

Zinc regulates iNOS-derived nitric oxide formation in endothelial cells. Zinc inhibits iNOS-dependent nitrite accumulation in endothelial cells. Zinc decreases cytokine-induced iNOS expression in endothelial cells. Zinc inhibits iNOS promoter activity. NF-kB silencing abolishes cytokine-induced iNOS expression. Zinc inhibits the transactivation activity of NF-κB. https://www.sciencedirect.com/science/article/pii/S2213231714000834

@Violeta @sb4

 

[Nord Wolf]

That's interesting. I was just wondering while being awake in the middle of the night what could possibly cause someone to be low in a number of neurotransmitters.

Thanks for the reminder. Yes we have Butyrate but I’ve been forgetting to take it. With my poor to absent vision I need to have all my supplements set on a shelf in a specific order so I know what to grab at what time of day. Most of the time my wife sets them out in order. Occasionally we get a box of new supplements and things get shifted… The Butyrate was moved and so I don’t think I’ve taken it for a couple months… I need to get back to taking it again.

Greg Nigh, ND, Lac wrote some great things about Butyrate in his book The Devil In The Garlic, a book about the issues with sulphur in foods.

studies have shown that people with ME/CFS tend to have lower levels of butyrate

I am seeing studies saying people with ME/CFS tend to have higher levels of BH4 in their blood than controls. This is said to cause higher than appropriate levels of nitric oxide.

Are you saying you've found different studies showing folks with ME have both higher and lower levels of butyrate?

 

[Violeta]

The sentence about higher levels refers to tetrahydrobiopterin, BH4.

I don't know how butyrate and Bh4 got into the same thread. I am sorry for the confusion,

My daughter's dog had to go to the hospital, started having tremors out of nowhere, having a hard time focusing.

 

[Violeta]

The sentence about higher levels refers to tetrahydrobiopterin, BH4.

I don't know how butyrate and Bh4 got into the same thread. I am sorry for the confusion,

My daughter's dog had to go to the hospital, started having tremors out of nowhere, having a hard time focusing.

Okay, they are both affect the level of tyrosine, an important constituent of neurotransmitters.

 

[Violeta]

Greg Nigh, ND, Lac wrote some great things about Butyrate in his book The Devil In The Garlic, a book about the issues with sulphur in foods.

That book looks really interesting!

Oh, good, Weston A. Price has the Cliff Notes for it!

https://www.westonaprice.org/health-topics/low-sulfur-diet-benefits/#gsc.tab=0

"Why do we need sulfate? For one thing, all of our connective tissue is heavily sulfated. In order to build collagen and connective tissue that have integrity, you have to add heparan sulfate molecules to it. These are called heparan sulfate glycosaminoglycans or proteoglycans."

This is so interesting, because I had just found out about the involvement of the epithelail lining of the gut.
I started taking fucoidan about a week ago. One of the important constituents of fucoidan is heparan sulfate!

What got me interested in this was @LINE's thread on butyrate.

 

[Violeta]

@Nord Wolf, have you seen the studies saying those with Parkinson's have higher levels of heparan sulphate than normal?

Have you or your wife tried the low sulphur diet recommended in the book?

I can't figure out why heparan sulphate, which is so absolutely necessary, would cause something so negative to happen. (See the study at the bottom of this message)

Another confounding thing is that heparan sulphate is necessary for the health of the gut and lung lining. But in Parkinson's,
Mucin is important for the integrity of the intestinal mucus layer and for the maintenance of intestinal barrier function. A decrease in mucin could contribute to the increase in intestinal permeability found in PD patients [65], [66].

The decrease might be due to too much Akkermansia bacteria. (Akkermansia in those with ME/CFS is lower than normal.)

The gut bacterium Akkermansia muciniphila (A. muciniphila) is a potential factor in Parkinson's disease(PD):

• Gut microbiota
  The composition of gut microbiota, including A. muciniphila, is altered in many neurological diseases, including PD. Multiple studies have found that A. muciniphila is more abundant in the fecal samples of people with PD.
  
  
  
• Alpha-synuclein (αSyn) aggregation
  In vitro experiments have shown that Akkermansia muciniphila can induce αSyn aggregation in enteroendocrine cells (EECs). αSyn aggregation is a key component of PD, as it can disrupt cellular homeostasis and lead to neuronal death.

Heparan sulfate proteoglycans mediate prion-like α-synuclein toxicity in Parkinson's in vivo models:​

https://pubmed.ncbi.nlm.nih.gov/35790300/

 

[Violeta]

According to this study, the Akkermansia led to alphaSynuclein aggregation in the absence of mucin in the gut lining.

And heparan sulphate is supposed to help with mucin lining. What is causing the mucin lining of people with Parkinson's to be deficient?

Akkermansia muciniphila induces mitochondrial calcium overload and α -synuclein aggregation in an enteroendocrine cell line​

"Our in vitro experiments showed that the protein-enriched fraction of mucin-free CM induces RyR-mediated Ca2+ release and increased mitochondrial Ca2+ uptake leading to ROS generation and αSyn aggregation. Oral administration of A. muciniphila cultivated in the absence of mucin to mice led to αSyn aggregation in cholecystokinin (CCK)-positive EECs but no motor deficits were observed. Noteworthy, buffering mitochondrial Ca2+ reverted the damaging effects observed. These molecular insights offer evidence that bacterial proteins can induce αSyn aggregation in EECs."

 

[Violeta]

And heparan sulphate is supposed to help with mucin lining. What is causing the mucin lining of people with Parkinson's to be deficient?

So if Parkinson's involved elevated heparan sulphate but diminished mucin on the lining of the gut, could it be that they are deficient in sialic acid?

Sialidases and fucosidases of Akkermansia muciniphila are crucial for growth on mucin and nutrient sharing with mucus-associated gut bacteria​

Research suggests a potential link between sialic acid deficiency and Parkinson's disease, with studies showing altered sialylation patterns (levels of sialic acid attached to glycoproteins) in the brains of Parkinson's patients, indicating a possible role in the disease's progression through mechanisms like neuroinflammation and impaired cell signaling; however, the exact nature of this relationship is still being investigated and further research is needed to fully understand its implications.

What produces sialic acid?

Sialic acid is synthesized by glucosamine 6 phosphate and acetyl-CoA through a transferase, resulting in N-acetylglucosamine-6-P. This becomes N-acetylmannosamine-6-P through epimerization, which reacts with phosphoenolpyruvate producing N-acetylneuraminic-9-P (sialic acid).

 

[Blazer95]

That's interesting. I was just wondering while being awake in the middle of the night what could possibly cause someone to be low in a number of neurotransmitters.

It's interesting, too, because studies have shown that people with ME/CFS tend to have lower levels of butyrate, and Standford is looking for people with ME/CFS to participate in a study about BH4.

I am seeing studies saying people with ME/CFS tend to have higher levels of BH4 in their blood than controls. This is said to cause higher than appropriate levels of nitric oxide. I'm going to have to look into that.

@Nord Wolf, did you see this?

So you are trying to Tell us increased 1,25-dihidroxyvitamin d is limiting dopamine ?