Alpha-synuclein having a role in ME?

[Wishful]

I finally came across a possible explanation for why cumin was effectively blocking my PEM: cuminaldehyde prevents fibrillation (agglomeration?) of alpha-synuclein. I followed that, and found that a-syn is a very common protein in the brain (1% of all protein in the brain) and is important for neural function. That seemed like it could possibly explain PEM. Luckily, there's plenty of information available about a-syn, since it's responsible for Parkinson's Disease.

Digging deeper, a-syn is influenced by microglial activation. Microglial activation seems to play an important role in my ME, so that fits too.

Another finding: red blood cells are the major source of a-syn in blood. Various research teams have found abnormalities in RBCs in PWME. Could a-syn be responsible for reduced deformability or the stress response measured (nanoneedle tests)? I can't answer that question, but maybe the experts can. I can't easily find a mention of the expected size of the 'something in the serum', but a-syn is carried around in exosomes as well as free particles.

Another possible link: "Serum from ME/CFS patients causes mitochondria that were fused together to fragment, whereas serum from healthy controls does not." A-syn has been found to affect mitochondrial fusing and fragmenting. From https://www.hindawi.com/journals/omcl/2019/4246350/ : "It has been reported that a fraction of soluble α-syn directly interacts with mitochondria-associated endoplasmic reticulum (ER) membranes (MAM) [4], influencing mitochondrial fusion and fission. Interestingly, α-syn aggregation produces mitochondrial fragmentation or mitochondrial respiration failure and death in cell-based models of PD." Thus it also seems possible that a-syn's effects on mitochondria could explain some of the findings in ME.

I'm not a trained biologist (plus I'm brainfogged) so I'm not up to following this much deeper. A-syn does seem to have a lot of possible connections to ME. Coincidence, or something more? I'm posting this so that some experts can think about it. One way of doing science is to think about the various pieces of the puzzle and see if any of them fit together. Maybe a-syn fits some other observations of ME.

Also, a couple of (I assume) cheap easy tests: run the RBC deformability test and nanoneedle test with the addition of cuminaldehyde, or one or more of the chemicals known to affect a-syn. Maybe it will show no effect, but what if it did? Seems a cheap gamble for a possible major payoff.

 

[Rufous McKinney]

Maybe it will show no effect, but what if it did?

Interesting theory worth further investigation!! Nice job getting- this far!

I'm unable to tolerate eating cumin. I don't think I can tolerate burping it either. So I wonder if this substance may exist- outside the whole herb.

 

[Rufous McKinney]

Thus it also seems possible that a-syn's effects on mitochondria could explain some of the findings in ME.

alot of fine print in that article!......

a friend of ours developed the Lewy's bodies version of Parkinsons. It was a very difficult thing.

His wife told me...that I'm not sick, its just all in my head. - Those stunning moments when your good friend insults you totally and you realize they so have NO CLUE.

So was that all in his head?

 

[Wishful]

So I wonder if this substance may exist- outside the whole herb.

Cuminaldehyde is available from chemical suppliers. It's also in cassia (Chinese cinnamon), eucalyptus, and some other plants; not sure about how much is in those, and the other constituents might cause problems. There are some other herbs that also reduce a-syn fibrillation; I think Chinese skullcap was one (active chemical Baicalein, IIRC). A search here shows other threads about skullcap. No one reported it as a PEM blocker, but I tried cumin for years before noticing that it was blocking PEM. It's hard to notice PEM-blocking if you keep avoiding PEM triggers, and it's also hard to notice events (PEM) that doesn't happen.

 

[ShepherdK]

Doing a quick literature review - there are plenty of compounds that inhibit fibrillation of alpha-synuclein. Seems like a pretty solid list of common supplements from this forum, actually.

• PQQ Inhibits a-syn fibrillation - this seems more specific to parkinson's
• Epigallocatechin Gallate (EGCG)
• Baicalein
• Nicotine
• Panax Ginseng (*RB1 specifically)
• Cuminaldehyde
• Rifampicin

 

[sb4]

cuminaldehyde prevents fibrillation (agglomeration?) of alpha-synuclein

Could you explain this a bit more? What is fibrillation in relation to a-syn?

How do you take curcumin and how much? Have you gone peroids without it and PEM has come back?

 

[xebex]

Cuminaldehyde is available from chemical suppliers. It's also in cassia (Chinese cinnamon), eucalyptus, and some other plants.

Fascinating stuff @Wishful, thanks! interestingly enough I get a lot of help for my migraines (which I’m certain are intertwined with my ME and possibly somehow causative as my migraine severity dropped once I got ME) by using eucalyptus.

 

[Wishful]

Could you explain this a bit more? What is fibrillation in relation to a-syn?

I looked for a good explanation, but googling 'fibrillation' just gets lots of links to heart disease. I think that for a-syn it means that the proteins clump together, which makes them unable to do their function and can block other cell functions (causing the plaques in PD, for example).

How do you take curcumin and how much? Have you gone peroids without it and PEM has come back?

Curcumin (at least turmeric) makes my ME worse. It's cumin (Cuminum cyminum) that worked reliably for me as a PEM-blocker. Here's the thread with all the details: https://forums.phoenixrising.me/threads/possible-pem-blocker.56232/

In short, a level tsp would block PEM 100% for three days. After two years of taking it every three days (and doing physically strenuous activities during that time), it seems to have cured me of PEM. It's been thee weeks since my last dose of cumin, and despite physical activities that should have caused PEM, I remain PEM-less.

I don't know why it works for me (blocking a-syn fibrillation is the only reasonable possibility I've found so far) and I don't know why it doesn't work for anyone else. I expect that if it doesn't block your PEM immediately, taking it for 2 years won't work either, but if I was suffering really badly from PEM, I think I might take it every few days just on the slim chance that it would eventually work. It's cheap and safe, and if you don't like the taste, there are ways around that.

I got a response from OMF about my suspicions about a-syn. They like the idea, and are passing it on to the researchers. Maybe soemthing will come out of it. An effective treatment (or cure!) for PEM wouldn't solve ME, but it sure can improve the quality of life.

 

[Wishful]

In another thread I described another possible link between a-syn and ME (or at least PEM). My PEM seems to have been triggered by using fast-twitch muscles, rather than slow-twitch. The two types of muscles differ in how much the mitochondria are linked together: "Both aging and chronic periods of muscle disuse result in an increase in fission, relative to fusion, regulatory proteins.72 This imbalance results in mitochondrial populations that are smaller and more fragmented, and tend to produce more ROS. " If extra a-syn (maybe in exosomes) was the 'something in the blood', it might be causing mitochondrial fragmentation in muscle tissue, and thus poor energy production and more ROS damage. A-syn also affect membrane construction and function, which affects cell function.

 

[Rufous McKinney]

I got a response from OMF about my suspicions about a-syn. They like the idea, and are passing it on to the researchers. Maybe soemthing will come out of it. An effective treatment (or cure!) for PEM wouldn't solve ME, but it sure can improve the quality of life.

Very cool! May I send you a bottle of Champaigne?!

 

[Wishful]

Better hold off until someone actually verifies that there's a real connection. It might just be coincidence.

Since cumin only worked on my physically-induced PEM, and not cerebrally-induced or my general ME symptoms, a-syn doesn't seem like the answer to ME in general. It does make me wonder if the patients who go to labs for testing tend to be experiencing PEM at that time from the effort of travelling to the lab, talking with medical personnel, etc. Maybe people with severe ME are suffering from some level of PEM constantly, so the various abnormalities found (RBC deformability, nanoneedle testing) could be measuring PEM rather than ME.

 

[Wishful]

I was going to suggest that those here with a particular interest in gut involvement in ME search for connections between a-syn and the gut. A quick check shows that yes, there does seem to be several possible links. Gut problems (dysbiosis and others) can cause fibrillated a-syn, which then spreads to the brain. It can also modulate immune response in the gut and elsewhere. This hardly proves a direct link between a-syn and ME (or just PEM), but it certainly looks like a possibility that should be checked out.

See: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6491838/

 

[ShepherdK]

@Wishful - very interesting - so one teaspoon has that much of an effect? Do you take anything else alongside it?

I might run a trial this week of putting 1tsp into pill capsules and taking them alongside my normal supplements and see if I can notice a difference. It would be interesting to see if there is a dose/duration change in effect as well.

 

[Wishful]

A level tsp, and yes, it's an impressively dramatic effect. I expected to have a really lousy PEM day after chainsawing a big tree, but no PEM showed up. One dose would block PEM completely for 3 days. Marvelous stuff, at least for me. Other people reported trying it and having no significant effects. I don't know why it works so well for me and not for others.

I didn't take anything with it, and time of day or taking with or without food made no difference.

I've mentioned it in this thread recently too (page 3): https://forums.phoenixrising.me/threads/describe-your-pem.15934/page-3#post-2257744

 

[Wishful]

Another possible link between a-syn and ME: sleep is important for clearing out waste products in the brain, including a-syn. Could ME involve dysfunction with this clearing system? There's even a positive feedback loop: ME could cause poor waste removal, which in turn would cause worsened sleep. Astrocytes are critical for this waste removal process, which means that they, and their functionality, would be affected by inflammatory processes, which are found in ME.

For those interested in cervical issues, the glymphatic system drains into the 'deep cervical lymph nodes'. I don't know if CCI affects those nodes (I assume it does), but that could explain why some people get benefits from treating CCI.


I also found this: "However, it is likely that, in the presence of macrophages and/or microglia, astrocytes become indirectly neurotoxic by the production of large concentrations of kynurenine that can be secondarily metabolized by neighbouring or infiltrating monocytic cells to form the neurotoxin QUIN."

My ME symptoms seem to involve kynurenine production by glial cells. The finding above could be the link between glial activation and ME symptoms (brain not clearing waste efficiently).

What I don't see is PWME reporting reduced symptoms if they manage to get some good sleep. A recent thread was about improvements by not getting enough sleep. That's not fatal counterevidence, since it's possible that ME makes our waste-pumping less effective or even counterproductive during deep sleep. Maybe the network is pumping backwards during sleep. There are probably ways to test this hypothesis by measuring lymph flows or waste product levels. This hypothesis would certainly fit the description of 'unrestful sleep'.

As with the rest of this thread, it's just suspicious links. Maybe it will trigger new lines of thoughts among researchers.

 

[ShepherdK]

@Wishful

Weird anecdote - I did something this weekend that usually gives me bad PEM: scrubbing my shower for 2hrs. I felt completely drained afterward, however I had enough energy to make four 00-size capsules of cumin powder. I took that, and now two days later I'm still fine - no PEM whatsoever. The cumin isn't making any of the other baseline symptoms / general condition better, however I think you might be onto something with blocking PEM in particular.

 

[Wishful]

Good, I hope it works well for you. Cumin didn't do anything for my other ME symptoms, but it was amazing for blocking or reducing my physically-induced PEM. Didn't work for cerebrally-induced PEM.

 

[Violeta]

Our data indicate that nitrative and oxidative insult may initiate pathogenesis of α-synuclein aggregates. (peroxynitrite)

Induction of α-Synuclein Aggregation by Intracellular Nitrative Insult
Evgenia Paxinou

https://www.jneurosci.org/content/21/20/8053

However,

A spirulina-enhanced diet provides neuroprotection in an α-synuclein model of Parkinson's disease
Mibel M Pabon

https://pubmed.ncbi.nlm.nih.gov/23028885/

 

[Alvin2]

Nilotinib has been used experimentally for Parkinsons.

I had done some research and found a similar method of action from Quercetin.
But its bioavailability is low. There is a form called EMIQ which has much higher bioavailability
But its half life is about 2 hours (iirc). You would need to take it several times day but if you can get it its worth a try.

All that said i don't think alpha synuclein has much to do with ME and i've been tested very extensively for Parkinsons and i don't have it
That said your causation may be different than mine and in the NIH study two ME/CFS patients were misdiagnosed, they actually had Parkinsons disease.

 

[Violeta]

Nilotinib has been used experimentally for Parkinsons.

I had done some research and found a similar method of action from Quercetin.
But its bioavailability is low. There is a form called EMIQ which has much higher bioavailability
But its half life is about 2 hours (iirc). You would need to take it several times day but if you can get it its worth a try.

All that said i don't think alpha synuclein has much to do with ME and i've been tested very extensively for Parkinsons and i don't have it
That said your causation may be different than mine and in the NIH study two ME/CFS patients were misdiagnosed, they actually had Parkinsons disease.

My reason for posting that here is that the original poster was noticing that A-syn seems to have a lot of possible connections to ME. Since peroxynitrite has been shown to have a connection to ME (Martin Pall), I thought that the information that peroxynitrite is what causes a-syn to form lewy bodies might be interesting.

At this point, I don't seem to have Parkinson's, either, but studies related to Parkinson's provide a lot of helpful information.