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Sunday, 11 July 2021

Leaky ATP from either Mitochondria or Neurons in Fragile X and Autism

 


 

For leaky ATP, Popeye might want to try Dexpramipexole and

Suramin, or even the already approved Mirapex


If you are old enough to be a parent, you will have encountered problems with some kind of leak.  A leaky roof, a leaky pipe, a leaky washing machine, an air-conditioning unit... The list goes on, the older you get.

I have been preoccupied by fixing a leak recently.  We have a large roof terrace and, in the winter, water started leaking from the ceiling in the floor below.  I improvised a system to catch all the water, but still I had to find the source of the leak.

I did finally find the source of the problem and most importantly without digging up 95% of the terrace.  Now I have to put the 5% back together again.

Leaks are often extremely difficult to locate, because water always finds the easiest path and the dripping you see might have originated from a leak far away.  Nobody wants to fix leaks, because it can be a pretty thankless task and you can cause plenty of damage in the process, without solving the problem.  So, as with fixing autism, I ended up doing much of the fixing myself.  The damage had actually been there since the house was built, hidden under ceramic tiles.

I recently read about leaky ATP in Fragile-X, where ATP leaks from the mitochondria into the cell.

This fits neatly into Professor Naviaux’s belief that ATP is leaking from the cell into the extracellular space, as the basis for his concept of the cell danger response, as a unifying and treatable feature of most autism.

Sounds complicated?

Just think of it as bunch of leaks you need to fix.

 

 What is ATP? 

ATP has many functions:- 

·        It is the fuel your cells need to function.

·        It is a signalling molecule within a cell and importantly between different cells.

·        It is used to make your DNA

  

Mitochondria

Each cell in your brain contains many mitochondria and these are where ATP is produced. Mitochondria die and are replaced, whereas if the host brain cell dies, it is lost forever. Cell death in the brain is bad news.


The ATP – ADP Cycle 

You can think of ATP as a fully charged battery.  Once the energy has been used up the flat battery is called ADP and it goes back for recharging in the mitochondria.  It is a continuous cycle.

ADP is powered back to ATP through the process of releasing the chemical energy available in food; this is constantly performed via aerobic respiration in the mitochondria. This process is also called OXPHOS and has been covered in previous posts.  In most mitochondrial disease the problem is that one of the four mitochondrial enzyme complexes is insufficient; this means that the ATP-ADP cycle is restricted.  There is then insufficient energy to power the brain in times of peak energy requirement.  This can cause loss of myelination and ultimately cell death.

 



  

ATP in Fragile X

It looks like in Fragile X the mitochondria in the brain do not work properly. ATP is leaking from the mitochondria and this stops synapses from maturing. 

A synapse is just the junction between one neuron and its neighbour.

The immature synapse manifests as autistic behavior.  When you plug the leak with Dexpramipexole, a drug trialed for ALS and now asthma, dendritic spines mature and autistic behavior is reduced.

To what extent this leakage occurs in idiopathic autism is unknown, but we know that impaired dendritic spine formation/morphology is a key feature of most autism and that it can be modified, although the sooner you start the better the result will be.

It looks to me that some people diagnosed with mitochondrial disease based on blood tests may actually have leaking ATP which then affects metabolic pathways and shows up with odd blood test results, that is then misdiagnosed as mitochondrial disease.  Note that many people diagnosed with mitochondrial disease show no response to therapy.

In Professor Naviaux’s theory, the ATP leak is from the cell membrane, like the outer wall of the cell.  He thinks that ATP is leaking and this then sends a false danger signal to the rest of your brain.  This is his Cell Danger Response (CDR).  Because the brain thinks it is under attack it is set in a permanent pro-inflammatory state, this gets in the way of basic functions the developing brain needs to complete.  This might explain why the microglia (the brain’s immune cells) are found to be permanently activated in autism; this then means that they do not carry out their regular brain housekeeping activities very well, like pruning synapses.

Naviaux wants to plug the leaks in the cell wall using Suramin, which is an old anti-parasite drug made by Bayer, the giant German company.

The link between the Fragile X research from Yale and Naviaux’s work at UCSD is that ATP needs to be kept in the right place for the brain to function correctly.

Leaky ATP will cause you big problems.

 

 

Now for the supporting research

 

Leaky ATP in Fragile X

 

Fragile X syndrome traits may stem from leaky mitochondria

The persistent leak influences which metabolic pathway the cell uses to generate energy, the team discovered by using a technique called mass spectrometry. For example, fragile X neurons produce more enzymes associated with glycolysis — a pathway commonly used by immature cells — than do typical neurons. Previous studies have shown altered mitochondrial metabolism in people with other forms of autism2.

Adding dexpramipexole to the cells of fragile X mice decreased production of lactate dehydrogenase and other enzymes linked to glycolysis, suggesting that closing the leak causes the neurons to start to use different, more mature metabolic pathways.

Giving injections of dexpramipexole to fragile X model mice lessened their hyperactivity, repetitive behaviors and excessive grooming — traits that are reminiscent of those seen in people with autism and in those with fragile X syndrome. Mice that received the dexpramipexole injections also had neurons with more mature dendritic spines and decreased levels of protein synthesis.

Dexpramipexole has been tested in people with the neurological disease amyotrophic lateral sclerosis and found safe, but it is unclear how it would affect young people if taken over sustained periods of time.

 

ATP Synthase c-Subunit Leak Causes Aberrant Cellular Metabolism in Fragile X Syndrome

Loss of the gene (Fmr1) encoding Fragile X mental retardation protein (FMRP) causes increased mRNA translation and aberrant synaptic development. We find neurons of the Fmr1-/y mouse have a mitochondrial inner membrane leak contributing to a "leak metabolism." In human Fragile X syndrome (FXS) fibroblasts and in Fmr1-/y mouse neurons, closure of the ATP synthase leak channel by mild depletion of its c-subunit or pharmacological inhibition normalizes stimulus-induced and constitutive mRNA translation rate, decreases lactate and key glycolytic and tricarboxylic acid (TCA) cycle enzyme levels, and triggers synapse maturation. FMRP regulates leak closure in wild-type (WT), but not FX synapses, by stimulus-dependent ATP synthase β subunit translation; this increases the ratio of ATP synthase enzyme to its c-subunit, enhancing ATP production efficiency and synaptic growth. In contrast, in FXS, inability to close developmental c-subunit leak prevents stimulus-dependent synaptic maturation. Therefore, ATP synthase c-subunit leak closure encourages development and attenuates autistic behaviors.

 

Highlights 

·        ATP synthase c-subunit leak in Fragile X causes aberrant metabolism

·        Changes in ATP synthase component stoichiometry regulate protein synthesis rate

·        Inhibition of the leak normalizes synaptic spine morphology and Fragile X behavior

 

In Brief

Lack of FMRP in Fragile X neurons is associated with a leak in the ATP synthase, the blockade of which normalizes cellular and behavioral disease phenotypes.




 

Now they fix the leak using Dexpramipexole (Dex) and cyclosporine A (CsA)



 



 

We have found that the mitochondrial inner membrane leak of FX neurons and cells is caused by abnormal levels of ATP synthase c-subunit. The c-subunit leak causes persistence of a mitochondrial leak metabolic phenotype characterized by high glycolytic flux, high lactate levels, and increased levels of glycolytic and TCA enzymes. The leak also aberrantly elevates overall and specific protein synthesis; a decrease in c-subunit level or pharmacological inhibition of the ATP synthase leak reduces protein synthesis rates and decreases the levels of leak metabolism enzymes. In Fmr1/y synapses, stimulation-dependent protein synthesis is absent. This is correlated with a lack of stimulus induced EF2 phosphorylation and a lack of synthesis of the ATP synthase b-subunit. These abnormalities are readily reversed by ATP synthase leak inhibitors, suggesting that leak closure is required for the ATP-dependent phosphorylation of EF2 adjacent to mitochondria. EF2 phosphorylation may regulate the change in subsets of proteins synthesized and may be correlated with- the overabundant synthesis of enzymes supporting a high flux glycolytic/TCA cycle ‘‘leak’’ metabolism indicative of metabolic immaturity. Consistent with the hypothesis that the c-subunit leak is also a major cause of synapse immaturity, we find that inhibition of the ATP synthase leak allows the maturation of synapses and normalizes autistic behaviors.

 

 

 

Closing Leaky Mitochondria Halts Behavioral Problems in Fragile X, Study Suggests


“In Fragile X neurons, the synapses fail to mature during development. The synapses remain in an immature state and this seems to be related to their immature metabolism,” she said.

The investigators tested whether closing the leak to boost the efficiency of ATP production would lessen behavioral abnormalities.

They first saw that nerve cells treated with an ATP synthase inhibitor named dexpramipexole (Dex) — a form of the common Parkinson’s therapy Mirapex ER (pramipexole) and previously tested as a treatment for amyotrophic lateral sclerosis — increased the levels of ATP.

Two-day treatment with Dex also reversed autistic-like behaviors, namely excessive time spent grooming and compulsive shredding of the animals’ nests. The treatment also reduced hyperactivate behaviors.

“We find that inhibition of the ATP synthase leak allows for the maturation of synapses and normalizes autistic behaviors in a mouse model of [fragile X],” the team wrote.

Jonas and her team now intend to further test the effectiveness of this and other leak-closing therapies for improving learning.

The lab is conducting a study assessing the role of leaky membranes in memory formation. Findings could pave the way for novel therapeutics for fragile X and autism, as well as for Alzheimer’s disease.

 

 

 

Dr Naviaux and Suramin for Autism

 

I have covered Suramin in previous posts.  There is a presentation below by Prof Naviaux that is for lay people, it is good to hear directly from the man himself.

 

Autism Treatment, the cell danger response and the SAT1 trial

https://youtu.be/pqd_BoCeRUw




In essence he says that when cells are stressed, they leak ATP and this creates the cell danger response.  If you have suramin in your bloodstream, it plugs the ATP channels and stops it leaking out of the cell and so blocks the cell danger response.



It is the cell danger response that is causing the symptoms we see as autism.

  

Conclusion

Who to call to fix an ATP leak?

If it is a case of Fragile X, there looks to be potential solution, but you will definitely not find it at your local doctor’s office.

For a mouse with Fragile X, you might choose Dexpramipexole.  Dexpramipexole was developed as a therapy for ALS (motor neuron disease), but failed in phase 3 trials and is now being developed for asthma.

For a human, the logical place to start would be the already approved Mirapex, which is currently used to treat Parkinson's disease and restless legs syndrome.

Mirapex - a miracle for Fragile X?

Clearly somebody should make a clinical trial of the existing drug.

I expect what will happen is that the Yale researchers will come up will a new drug that can be patented as a novel therapy for Fragile X.  This way they get to make some money, but a decade is wasted.

Is leaky ATP from mitochondria an issue in broader autism, beyond Fragile X? That is still unknown, but the Yale researchers seem to think their work has potential application in both autism and Alzheimer’s.

In the case of broader autism, Dr Naviaux and his partner Kuzani have some competition from Paxmedica.  Both groups seek to monetize Dr Naviaux’s published research.

It looks like the German giant Bayer does not want to help either group.  Instead of just tapping into Bayer’s existing production of Suramin, Kuzani and Paxmedica will have to figure out how to produce Suramin.

This all helps us to understand why there still are no approved therapies for core Autism or indeed Fragile X and yet there is a mountain of research.  Too many barriers and interests to overcome.

If you want to fix leaky ATP any time soon, you will be doing it mainly by yourself.  This has been my experience with most other kinds of leak!

 




 

27 comments:

  1. Hi Peter have yuo tried Mirapex or are yuo thinking to try?

    ReplyDelete
    Replies
    1. Diego, no I have not tried Mirapex. It does look interesting for those with blood tests that Dr Kelley says indicate mitochondrial disease, but do not respond to his therapy. It would be best to get some thoughts from the Yale researchers as to who might benefit.

      Delete
  2. I remember reading an interview done with Prof Naviaux a few years back, he seemed to imply Cell Danger Response was like a switch that can be potentially turned off permanently.

    So, the patient would only need to take Suramin for a short period of time to see permanent benefits.

    Since Suramin is quite toxic over time and not something you can take permanently as a regular drug like bumetanide, if it’s a temp plug to fix a Mitochondria leak that quickly wears off, I’m not sure how sustainable that will be long term?

    Hopefully I’ve got it wrong & he knows what he`s doing, I found this link showing success in phase 2 trials of suramin for autism. Its frustrating how slow these things are! suramin benefits were noticed many years ago now who knows when phase 3 will be?.

    https://www.prnewswire.com/news-releases/paxmedica-announces-positive-results-from-phase-2-trial-of-pax-101-iv-suramin-in-children-with-autism-spectrum-disorder-asd-301224425.html

    ReplyDelete
    Replies
    1. Ross, the effect of Suramin seems to last only a few weeks. Its effect then falls below the level where it plugs the ATP leak.

      The original idea was to find a safer drug that has the same effect on ATP channels as Suramin, then it was decided that Suramin was not to toxic after all.

      Delete
    2. I watched a presentation by Weisman from Paxmedica a few weeks ago. After 3 monthly doses, they had sustained improvement 6 weeks after the last dose. They also had a lovely graph showing the difference between the placebo and therapy group, which was clear as day. To me, this sounds rather good, so far. Maybe they got the dosage and number od therapies right this time. They have also struck a deal with the FDA / they will have a multicenter study next year and if it goes really well, they will get the same type of licence as the current covid vaccines.

      Delete
  3. Do you know if there is research on Mirapex and ATP? I did not find anything in a quick search, but this is far out of my expertise.

    ReplyDelete
    Replies
    1. Sara, best to search for Dexpramipexole and ATP. There you will find plenty.

      Ideally they would investigate Dexpramipexole, but it is not an approved drug for humans, but it was in phase 3 trials.

      The researchers tell us that Dexpramipexole is closely related to Mirapex, which is off patent and not expensive.

      Delete
  4. Hi Peter, do you have any idea what dose of Miriapex to start with? Is there anyone who has made or knows how to make a prescription for suramin nasal spray? I found a site about pramipexole that says it repairs depression and even permanently ..... Peter what your opinion.https://pubmed.ncbi.nlm.nih.gov/15549689/

    ReplyDelete
    Replies
    1. Dragos, Pramipexole contains two isomers/versions, consider as left-hand and right-hand. The chemical formulas are the same, but one is the mirror image of the other.

      The S enantiomer (left-handed) is a potent dopamine D3/D2 receptor agonist and this why Pramipexole is extensively used in the management of Parkinson’s Disease. In contrast, the R enantiomer (Dexpramipexole) is virtually devoid of any of the dopamine agonist effects. The R enantiomer (Dexpramipexole) is the research drug used at Yale to treat the ATP leak from mitochondria in Fragile X.

      Both the S and R enentiomers of Pramipexole do share some effects in common.

      Pramipexole (the mixture of S and R types) has been proposed to exert a broad spectrum of neuroprotective properties, primarily through antioxidant effects, inhibiting apoptotic enzymes and preserving mitochondrial structure and activity.
      Due to the presence of the S enantiomer, the mixed version of pramipexole has high dopaminergic receptor activity and, consequently, dose-limiting side effects, including hypotension and hallucination. 100% Dexpramipexole exhibits significantly lower affinity for dopaminergic receptors, thereby making it unlikely to be associated with dopaminergic side effects.

      In the perfect world for Fragile X you would only use the R enantiomer.

      The generic drug is called Pramipexole (Mirapex), there is no mention of R- or S-, so it is likely to be a “racemic” mixture, which would contain 50% Dexpramipexole and 50% of the S enantiomer that you do not really want.

      You would want to avoid negative dopamine effects. This would vary very much from person to person, because some people with autism do have dysfunctions related to dopamine. If there ever is a clinical trial using Pramipexole, you would expect them to start cautiously with a low dose to see what happens.

      Delete
  5. This is a great post and easy to read, thank you Peter!

    ReplyDelete
  6. Please what dose of roflumilast would you recommend for a boy of 7 weighing 25kg.I was able to get 500mcg tablets.What quantity of vodka do I need to dilute in?Thanks

    We are using broccoli ,low dose clonazepam,guanfacine and pentoxifylline which he takes in the morning and guanfancine at night .I want to add roflumilast as in your recent post you mentioned about it being beneficial in addition to pentoxifylline .

    We have had vocal stimming and very bad throat clearing which I have treated with a 5 day course of prednisone but still no changes .I am thinking the throat clearing could be as a result of hay fever but he takes Tavegil too at night .What are your thoughts please .We have had so much cognition and his receptive has improved so much but we still have the speech problem but he is using pecs very well now and we are hoping to start an after school aba programme during the holidays using students at our local university.

    Please what could be the cause of the throat clearing he has also had his tonsils removed .Thanks
    Apinke

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    Replies
    1. Apinke, repeated throat clearing is a common vocal tic, but it can have a simple biological explanation. Allergy and acid reflux are known triggers for this tic. Since it is now summer where you live, allergy is quite possible, even though you use clemastine. Reflux is common in children with autism and is a trigger for aggression in some.

      Reflux is a common side effect of some drugs and can cause symptoms that might surprise you, they include coughing and throat clearing.

      Reflux is also a common GI symptom in autism. Reflux is treatable.

      I use an old 30ml propolis bottle with a screw on pipette top. I dissolve each 500mcg Daxas in 3ml of alcohol (vodka). 5 drops would be about 25 mcg, this would be a good dose to try. The effect is on cognition. It will be most noticeable during school time.

      Delete
    2. Apinke, my daughter has Pans. It is barely held back from its worst form by constant antibiotics and antifungals and monthly IVIG. vocal tics is how it started.
      In my experience, it goes like this - you subdue the immune system to a degree, your child jmproves in autism to a degree and then a dormant virus roars its head, and causes pans/pandas. I have been on this seesaw with ehr for 2 years now. Maybe you recognize that pattern too?

      Delete
    3. Thanks so much Peter .I will start the Roflumilast.I will see the gp and see if he can get treated for reflux but the default answer is likely to be that its part of his asd as thats how all the symptoms are explained .

      Thanks Tatjana I will read pandas symptoms again but here they don't treat pans except one goes private.Our NHS groups it as part of asd symptoms.
      Apinke

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    4. There is a big patient advocscy group for pans pandas in the UK and they have thousands of members. I think they can help you find solutions.

      Delete
    5. In the UK it depends where you live. Some people do get IVIG for free as a PANS therapy. It is expensive so you need to be assertive. Some people go private because their GP does not help.

      Delete
  7. Wow, this is super interesting, thanks for writing these posts! I am a high-school student who is interested autism and neuroscience, do you think we could hop on a quick zoom call to discuss what you do? Your blog really inspired me :)

    - Dhruv Balaji

    ReplyDelete
    Replies
    1. Dhruv, this blog is not something most scientists or doctors approve of, so it is not the best thing to read.

      Neuroscience and medicine are very conservative and cautious. If you want a career in one of these fields, you have to adopt their approach to be successful.

      Delete
    2. I’m interested in more than what is commonly known about autism, which is why I want to talk with you. I understand that what you write about isn’t common in medicine or neuroscience, but I still want to know it. Let me know if we can chat.
      - Dhruv

      Delete
  8. I do hope Prof Naviaux theory is correct, Mitochondria problems look realistically a whole lot more fixable than brain malformation, so its a big hope pathway.

    Although some good trusted scientists like Dr. Manuel Casanova point to & have evidence for brain malformation as a leading cause of idiopathic autism so i am confused how Mitochondria on its own could be a cause unless you go down the many autisms theory.

    ReplyDelete
  9. On a side note, Peter - our daughter was acting off after her last IVIG a few days ago. Her Pandas was very much worse. We were stumped and then discovered that one of her lower teeth is ready to change and wobbling. Of course ibuprofen will be added - do you think I should also give Sytrinol a try? Any other recommendations?

    ReplyDelete
  10. I know that folks in the US have experienced difficulties sourcing high quality NAC. Jarrow Sustain is no longer available as far as I can tell. So I thought I’d share that we ordered some from Nootropics Depot. No sulfur smell, unlike all of the NOW brand capsules I’ve tried recently. They actually didn’t sell NAC for awhile because they test all of their materials on receipt and found that their suppliers were providing degraded product, but say that they have now found a reliable source,

    ReplyDelete
  11. Hi Peter

    There was a recent lancet article link in spectrum news, regarding mitochondrial disorders & autism.

    https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(21)00267-X/fulltext

    ReplyDelete
    Replies
    1. Ross, that is a really thorough paper covering much more than autism.

      Energy metabolism clearly is disturbed in many neurological disorders. It is one of my pet subjects. Very many things can limit available power output in the brain.

      Delete
  12. Hi Peter,
    I did a second trial with Miccil.I got it from Mexico.
    Did 2mg for my son who weighs 60lb.No changes.Decided to discontinue.Trail lasted for 6 weeks.
    Last time I did the trial was 4 years ago with 1mg.At that time too there was no effect.Getting Miccil from Mexico is pretty expensive with the shipping costs that online pharmacies charge.
    Not sure how much it costs in Europe.
    Thanks
    SD

    ReplyDelete
    Replies
    1. SD, well at least you now know for sure that you are not missing out on a useful therapy.

      Online pharmacies clearly are overcharging people.

      In Europe the cost of a 1mg tablet of bumetanide in a retail pharmacy is about 10 cents. The problem most people have is they cannot get a prescription.

      Delete

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