Boosting p53 as a treatment of core ME/CFS pathology?

[Jesse2233]

Tumor protein p53 has been described as "the guardian of the genome" because of its role in conserving stability by preventing genome mutation. It appears to also repair damaged mtDNA (DNA specific to the mitochondria).

From a 2012 paper in the American Journal of Pathology:

The p53 within the cell is helpful in maintaining normal mitochondrial function because p53 in the mitochondria enhances base excision repair of mtDNA damage, and a loss of cellular p53 reduces mitochondrial function.

In a talk given by Dr Alan Light on 2/1/2017, he discusses yet to be published findings that acquired mtDNA mutations were found present in 39 out of 40 ME/CFS patients. Cort has a good summary here.

This 2011 study from Johns Hopkins links ME/CFS severity in part to GPR41, a gene involved in p53 signaling. These findings tie into Dr Gerwyn Morris' 2012 hypothesis that the loss of p53 is a key mechanism in ME/CFS.

I've not seen this discussed anywhere on PR, but perhaps boosting p53 can treat the core pathology of the disease.

How might we do this?

1. There is a Chinese cancer drug (edit: gene therapy) called Gendicine which is designed to treat patients with tumors who have mutated p53 genes. It does this via a recombinant adenovirus engineered to express wildtype-p53. This in turn over-expresses genes coding for the p53 protein, and, in my laymen's understanding, boosts p53. Its side effects seem to be relatively mild.
   
   Unfortunately this drug is only approved for use in China although I imagine there are ways to acquire it.
   
   
2. A 2003 study in Nature reports that interferon gamma / beta stimulates p53 synthesis.
   
   There has been a plethora of discussion on this board about ways to induce interferon and various studies and anecdotal stories showing benefit. For example: Dr John Chia's use of interferon to achieve full (albeit temporary) remissions, and the demonstrated effectiveness of Ampligen (an interferon inducer) to bring about near remissions.
   
   Perhaps these drugs are effective (in part) because they stimulate p53.
   
   
3. Finally a 2006 study from China shows that oxymatrine (another Dr Chia mainstay) up-regulates p53.

Caveats:

• A 2017 study published in BMC Medical Genetics (discussed here) found little evidence of mtDNA damage in ME/CFS patients.
  
  
• In 2016 Dr Ron Davis mentioned that "ME/CFS patients have a marked decrease in some of the Citric Acid Cycle metabolites while mitochondrial mutations generally cause an increase."

But it seems Dr Davis and the BMC researches were looking at mtDNA mutations present at birth and not the type of acquired mtDNA mutations found by Dr Light.

Almost all of this is above my head and I could be making some key misconceptions, so I'd love to get the feedback of those with a science background

Tagging some potentially interested folks:

@alex3619 @Valentijn @Hip @nandixon @alicec @halcyon @Tunguska @JaimeS

Thanks!

 

[JaimeS]

Very interesting. I would love to see Light's work published -- hopefully we can get a look at that data.

IFN is an interesting therapeutic target. I think we've got a Janus-faced disease, with some immune function upregulated and some suppressed. I worry that we may actually be looking at a condition of primary immunodeficiency with some compensatory mechanisms cranked up; and that what is 'cranked up' may depend on the individual. For example, I wouldn't consider it out of the question for interferon to be high in some ME/CFS patients...

e.g. Hornig's 'early phase' hypothesis: http://brainimmune.com/high-blood-i...-the-early-phase-of-chronic-fatigue-syndrome/

But it may be more than just that. Perhaps we'd see differences in age, gender, severity, onset trigger, etc.

Long story short, I wouldn't even try IFN as a therapy unless I knew for certain that mine was consistently low. I'd check out the side-effects, which I hear are substantive. And then I'd make my choice.

FWIW...

 

[Hip]

Very interesting idea. But as you say, @Jesse2233, there is little evidence of mitochondria DNA (mtDNA) damage in ME/CFS. (EDIT: I initially misread your post; so in fact there is evidence of mtDNA damage in ME/CFS).

Such mitochondrial DNA damage has been found in Gulf War Illness (GWI) patients, so boosting p53 in order to try to promote mtDNA repair in GWI might well be an interesting experiment.

Exposure to organophosphate pesticides, as well as exposure to low levels of organophosphate chemical warfare agents during the destruction of chemical munitions factories in Iraq, remains the leading contender for the cause of GWI. Pesticides are known to cause mtDNA damage, so it is perhaps therefore not surprising that such damage has been found in GWI patients.


My own case of ME/CFS was preceded by a major chronic exposure to organophosphate pesticides in my own home (as well as the contraction of a nasty virus), so the idea of trying to boost mtDNA repair is of interest to me.

I found the following supplements and drugs that boost p53:

Tumor Protein p53 Boosters:

• Vitamin B6 activates p53. Ref: 1
• Vitamin C up-regulates p53. Ref: 1
• Vitamin E up-regulates p53 and down-regulates the undesirable mutant p53. Ref: 1
• Tocotrienols (a form of vitamin E) activate p53. Ref: 1
• Hesperidin (citrus flavonoid) induces p53. Ref: 1
• Indole-3-carbinol (I3C) is a supplement that boosts p53. Ref: 1
• Calcitriol (the active form of vitamin D, available as a drug) induces p53. Ref: 1
• Vitamin C and sulindac synergistically induce p53. Ref: 1
• Kevetrin (thioureidobutyronitrile) is a drug which induces p53. Ref: 1

Plus you found that oxymatrine boosts p53. Ref: 1

And according to this article, vitamin D, zinc and selenium support p53.

The p53 protein is cleaved and fragmented in ME/CFS patients (ref: 1), which may inhibit its functioning (so boosting p53 to overcome this may be of benefit for ME/CFS).

And I came across this study which found that "the tumor suppressor protein p53 translocates to mitochondria and facilitates mtDNA mutation repair and mitochondrial biogenesis in response to endurance exercise." So endurance exercise might potentially be a useful way of treating GWI, although its use might be very limited by the fact that like ME/CFS patients, GWI patients also suffer from PEM.


By the way, it looks like gendicine is not a drug, but a modified adenovirus designed to deliver genes to cells, so it is a gene therapy.

 

[Jesse2233]

I worry that we may actually be looking at a condition of primary immunodeficiency with some compensatory mechanisms cranked u

Hmm, might immune deficiencies be caused by Krebs dysfunction, i.e. low NKC function?

For example, I wouldn't consider it out of the question for interferon to be high in some ME/CFS patients...

Good point. As it so happens I recently tested at 3x the upper range for interferon gamma. And Dr Chia told me that he's seen Hep C patients develop ME/CFS after interferon treatment

Long story short, I wouldn't even try IFN as a therapy unless I knew for certain that mine was consistently low.

That's understandable

But as you say, @Jesse2233, there is little evidence of mitochondria DNA (mtDNA) damage in ME/CFS.

True, but there's also little serological evidence it isn't

Exposure to organophosphate pesticides, as well as exposure to low levels of organophosphate chemical warfare agents during the destruction of chemical munitions factories in Iraq, remains the leading contender for the cause of GWI.

Interesting. How do GWI symptoms compare with ME/CFS? Any subtantially different lab findings?

I found the following supplements and drugs boost p53:

Beautiful!

By the way, it looks like gendicine is not a drug, but a modified adenovirus designed to deliver genes to cells, so it is a gene therapy.

You're right nice find

 

[Jesse2233]

Here's a link to an assay that tests p53 activation in nuclear extracts. Not sure how someone without access to lab would have this tested though. Maybe through an oncologist?

 

[Hip]

Interesting. How do GWI symptoms compare with ME/CFS? Any subtantially different lab findings?

I don't know that much about it, but GWI is symptomatically quite similar to ME/CFS.

 

[Jesse2233]

According to this paper from The Journal of Immunology it seems p53 is also involved in the regulation of B cells:

Several findings, involving both human and mouse B cells, show that a mitochondria-dependent apoptotic pathway involving p53 contributes to the high activation-induced cell death (AICD) susceptibility of replicating blasts

@Jonathan Edwards might decreased p53 expression have significance in autoantibody etiology or is this immuno-babble?

 

[Jonathan Edwards]

According to this paper from The Journal of Immunology it seems p53 is also involved in the regulation of B cells:


@Jonathan Edwards might decreased p53 expression have significance in autoantibody etiology or is this immuno-babble?

p53 is involved in all cells, like water or glucose. I cannot see any reason to think 'boosting' it would have any effect autoimmunity.

 

[Valentijn]

In a talk given by Dr Alan Light on 2/1/2017, he discusses yet to be published findings that acquired mtDNA mutations were found present in 39 out of 40 ME/CFS patients. Cort has a good summary here.

I don't see an explanation of why they believe the mutations are somatic, versus heteroplasmic. In fact, I don't even see their basis for saying that the mutation is sporadic in the patients, versus universal.

Their classification of the mutations is a bit suspect too. A stop-gain (nonsense) mutation can have a huge impact ... but it can also have no impact, especially if it's near the end of the gene. And missense mutations can range from having a severe impact to none at all, so the classification of all missense mutations as having "moderate" impact is not helpful.

It's also not clear regarding the source of controls. A mitochondrial mutation can easily be rare enough that a small study won't have it in the controls, but still be extremely common in people with maternal ancestresses from a specific region. So it can also be helpful to look at the prevalence from large compilations of genetic data, such as from 1000 Genomes.

Most of my questions will probably be answered in the research paper once it's published, but there's too many unknowns currently to speculate regarding those findings, so it would seem premature to try any treatments.

Tumor protein p53 has been described as "the guardian of the genome" because of its role in conserving stability by preventing genome mutation. It appears to also repair damaged mtDNA (DNA specific to the mitochondria).

p53 is very interesting. I'm curious as to how it recognizes DNA as damaged, and therefore intervenes to repair it. Mutations are extremely common and usually normal in mitochondrial DNA, and are widely used to determine ethnic maternal origins. So obviously it doesn't repair every change. I'm not up to reading in-depth currently, and couldn't find that sort of detail from skimming.

Another concern would be that if there is genetic involvement with p53, we don't have a clear indication if it's being over-active or under-active. If problems were caused by p53 getting too enthusiastic and mistakenly targeting healthy cells, or doing damage by targeting too many flawed but functional cells, there would be a risk of aggravating a problem instead of improving the situation.

This 2011 study from Johns Hopkins links ME/CFS severity in part to GPR41, a gene involved in p53 signaling. These findings tie into Dr Gerwyn Morris' 2012 hypothesis that the loss of p53 is a key mechanism in ME/CFS.

These are both extremely flimsy foundations to tie p53 to ME/CFS pathology. The first study was simply looking at the expression of 300 genes in Fukuda patients, and did not correct for making multiple comparisons. Hence it is almost certain that few or none of the results were statistically significant.

As for the second paper ... ME/CFS hypotheses are a dime a dozen, and I can't read anything at all into it. We need solid research, not musings. And they've had 5 years to turn those musings into solid research, but apparently not done so.

 

[Hip]

In a talk given by Dr Alan Light on 2/1/2017, he discusses yet to be published findings that acquired mtDNA mutations were found present in 39 out of 40 ME/CFS patients. Cort has a good summary here.

Sorry, I missed the above sentence the first time I read your post. So in fact there is evidence of mitochondrial DNA damage in ME/CFS.

In addition to this mtDNA damage sometimes being caused by exogenous toxins such as pesticides, perhaps in ME/CFS patients, mtDNA damage might also arise from the increased oxidative stress that mitochondrial dysfunction can produce.

So in ME/CFS, you might get non-genetic mitochondrial dysfunction first (eg, say by an autoantibody blocking the mitochondria), but then the increased oxidative stress this dysfunction produces might result in genetic damage to the mtDNA, thus exacerbating the mitochondrial problems, and worsening the ME/CFS disease process.



It's worth noting that in Parkinson's, a disease caused by death of dopaminergic neurons in the brain, mtDNA damage has been found in these neurons, and it appears that in Parkinson’s, these neurons are unable to properly repair the mtDNA damage. This may be part of the problem in Parkinson's disease. Like ME/CFS, Parkinson’s is another disease linked to pesticide exposure.

So perhaps your idea of up-regulating p53 to try to promote mtDNA repair might have application in Parkinson's, as well as possibly in ME/CFS.

Although this study suggests that the effects of p53 may be part of the cause of Parkinson's, as p53 can induce apoptosis, which might then lead to excessive death of dopamine neurons. So from this perspective, up-regulating p53 in Parkinson's might be a bad thing.

 

[Valentijn]

Sorry, I missed the above sentence the first time I read your post. So in fact there is evidence of mitochondrial DNA damage in ME/CFS.

No, at this point there's just a claim of damage. There's been no indication of how they determined that the mutations are from damage versus inherited. And the method they use for labeling the severity of mutations, as described in the video, isn't particularly meaningful.

We need to see the research before we can determine what the evidence actually shows.

 

[Jesse2233]

Agree that findings are preliminary and somewhat contradictory

FWIW I believe the Lights are still accepting blood samples from patients to be part of their study

 

[Hip]

Just came across some interesting papers relating tumor protein p53 to antiviral immunity. This antiviral effect of p53 may well be of significance in ME/CFS.

As you indicated above, @Jesse2233, interferon induces p53, and this paper says that interferon induced p53 contributes to apoptosis (cell self-destruction) in virally infected cells, and that such cell self-destruction is successful in impeding the replication and spreading of a wide range of viruses.

The paper also mentions that many viruses make proteins that block the action of p53, presumably in order to disable the antiviral p53 triggered apoptosis and thereby prevent the destruction of virally infected cells.



So this makes me think that boosting p53 could help fight some of the viruses found in ME/CFS patients.

Oxymatrine already up-regulates p53, but augmenting oxymatrine's effects by also taking some of the p53-boosting supplements detailed above might improve oxymatrine's efficacy in clearing viral infections. The paper says that:

p53-dependent apoptosis has been demonstrated as a useful mechanism to control some virus infection, as shown for VSV, influenza A virus, herpes simplex virus (HSV), or poliovirus.

The fact that p53-dependent apoptosis is antiviral for poliovirus (an enterovirus) suggests that p53 might also be antiviral for the enteroviruses linked to ME/CFS, namely coxsackievirus B and echovirus. And indeed, this paper finds that p53 is involved in the apoptosis response to coxsackievirus B5.

Although obviously one would not want to boost apoptosis too much, as you might then start killing too many cells.



Interestingly enough though, the paper points out that for some viruses, p53-dependent apoptosis actually boosts their replication:

In sharp contrast other viruses have evolved mechanisms to use p53 activity in its own benefit. Thus, p53 enhances the ability of human cytomegalovirus (HCMV) to replicate in fibroblasts, increases respiratory syncytial virus (RSV) or adenovirus replication and its absence has a detrimental effect in the growth of encephalomyocarditis virus (EMCV) and parainfluenza virus.

A possible explanation for this striking observation is that, while early apoptosis is probably detrimental for replication of some viruses, other viruses may benefit from apoptosis late in the replication cycle in order to improve transmission of newly-formed viral particles to other cells or hosts.

So any ME/CFS patients with active cytomegalovirus infection may not benefit from boosting p53, as this might worsen their infection.



Another interesting paper on the antiviral mechanisms of p53 says that the dsRNA created from a viral infection likely down-regulates p53.

Since the non-cytolytic enterovirus infections that Dr Chia thinks play a major role in ME/CFS actually comprise dsRNA (as well as ssRNA), this makes me wonder whether this enterovirus dsRNA might serve to prevent non-cytolytic enterovirus-infected cells from being destroyed by p53-triggered apoptosis. In which case, up-regulating p53 might again be useful for fighting these non-cytolytic enterovirus infections.

 

[Jesse2233]

Very interesting @Hip. It seems that p53 is quite the multifaceted protein. I wonder how one might gauge how much to increase p53 before it becomes detrimental

 

[Hip]

I wonder how one might gauge how much to increase p53 before it becomes detrimental

I know that in coxsackievirus B related diseases like myocarditis, excessive apoptosis is considered to be part of the pathogenesis of the disease, and often researchers look for ways of limiting apoptosis.

And as far as the type 1 interferon response is concerned, interferon can trigger apoptosis, but interferon also has other less destructive ways of dealing with virally infected cells, such as inducing the release of antiviral compounds like RNase L in the cell, which fight viruses without destroying the cell.

 

[Jesse2233]

Email I sent Dr Light

...I was wondering if you think boosting expression of p53 (a protein that repairs mtDNA) might be an effective line of treatment. I found studies that indicate oxymatrine and interferon both increase p53 levels. There is also a gene therapy treatment for cancer called Gendicine used in China to express wildtype-p53....

And his response

P53 is a complicated group of isoforms with many different functions, the most notable of which is tumor suppression (hence the Gendicine). Not sure I would mess with it unless there way to know your levels of the various isoforms. With as many as 30 different isoforms, this is probably not possible.

 

[Jesse2233]

Additional correspondence with Dr Light regarding the specific mtDNA complex to test

From me:

I'm seeing a local mitochondrial geneticist soon. Is there a specific test I could ask him to run that might correlate with your findings?

From Dr Light:

Yes, if he could test for substantial decreases in protein in mito Complex 1 it would be interesting to us. Also most of the other complexes could have decreases in proteins as well, but less severe.