General / Off-Topic Open Info:

[Robin of Spiritwood]

I'm going to post an outline of what the research says, and what we figured out, scaled down for laymen. This is to get it into public domain, and for general interest.

This is a picture of a cell.

The purple blob in the middle is the nucleus. That's where the DNA is.
The DNA is a very long single molecule, made up of repeating bits stuck together. Like a chain of Legos. Such a structure is called a "Polymer" .

If we were to take out the DNA from one of our cells, and stretch it out, it would be 1.5 km long. And it's all code, at a very very tiny molecular level. So there's a LOT of code.

Back in the 50's a lady scientist named Rosalind Franklin crystallized DNA, and took X-Ray pictures of it, and worked out how it was put together. She died of cancer related to the X-ray work, and never got the credit, which went to Watson & Crick. They went on to get a Nobel. And one of them lectured to my dad, using a bike chain to demonstrate a double helix, in Canada where he studied. So, dad knows this stuff better than me.

Everybody knows about that double helix today. But in case you do not, here it is.

The body has to keep the DNA code intact. In every single cell. The code takes incoming damage and develops up to 1,000,000 errors per day, along the length. The repair systems have to get that fixed, within seconds or even less time, per error, or we die.

There are different kinds of breaks that the helix can suffer, but for simplicity, we can split it up into 2 major categories:

• breaks in the crosslinks ( the base pairs)
• breaks in the backbone ( the "rails" of the helix)

Here's a ladder.
If we unwind the DNA, that is what we get. The breaks occur either in the steps, or the long vertical bars.

The problem we have is not is the steps, but in the long backbone. So there are basically 2 kinds of those:

• One side break
• Two sides break

Now I got to go fix some bloke's eye, and will explain more later. But in Parkinson's, there's a mix up between the 2 kinds of repairs for these breaks, that causes the disease.

 

[Robin of Spiritwood]

Ok-

Imagine you had a broken ladder to fix. But you were a blind handyman, the way the DNA repair systems are. The first thing you might do is run your hand over the ladder to find the break. Is it one side, or two?
A master Handyman might be able to fix a completely broken one, and a lesser Handyman could be trusted to handle a half-way broken one.

The lesser Handyman is the PARP enzyme family, which fixes the one-sided breaks.
The Master Handyman is a protein called Alpha-synuclein. Double strand break specialist.

Alpha-Synuclein seems to have a number of other jobs.
But we do know for sure that when people get Parkinson's, cells in the brain die, and they have clumps of alpha-synuclein in the cytoplasm. That's the hallmark of the disease. That's how a pathologist can take a bit of brain, look at it under a microscope, and say, "Aha, obviously, it was Parkinson's.". So these clumps have gotten the blame for the illness. They have a name "Lewy Bodies" and some research is underway to find out how to get rid of them- of course, that approach is doomed to fail to give anything useful for the disease. The Lewy Bodies are not the cause. They are a symptom.

See what they look like here.

The same finding occurs in a kind of Dementia related to Parkinson's.

Here's the important question:
If the alpha-synuclein is supposed to be fixing the DNA in the nucleus, what the flarkin is it doing outside, in a bunch of clumps??? And more importantly, what is fixing the DNA if the alpha-synuclein is absent??? The answer to that last one is, of course, NOTHING, which is why the cells are dying.

The thing we figured out is a way the alpha-synuclein is getting messed up, and how the Lewy Bodies are getting formed.
But before we can understand that, we have to understand the lesser Handyman's job- and that's PARP.

 

[Robin of Spiritwood]

Understanding PARP

Ok - so PARP is a family of related proteins. There are IDK exactly, 10? 17? of them. The jury is still out on what to include. But what they do is very very clear, because we've been looking at them for over 20 years now.

PARP fixes single strand breaks in DNA.

Now consider what that job is like.
- You have to cover 1.5 km of DNA. The breaks can happen anywhere. You are the size of a speck. And you have say 1.3 seconds to find and fix it, 24 hours a day.
The only way that could possibly happen is if there's a crapton of PARP molecules, all along the DNA strands.

So when I go through the chemistry, you have to consider that there is a fair amount of the reactions, occurring at different sites on the DNA all the time, just running 24/7. This is a vital metabolic function of every cell in the body. Once it gets messed up, the cell shuts down- either it dies, or it mutates and probably turns cancerous, or it stops working and goes into a zombie state called senescence.

So here's what PARP does- it finds a break, and then it sticks to proteins attached to the DNA near the break. Then it basically sets up a distress signal for other enzymes to come in and fix it.
It's sort of like a road flare, dropped at the site of an accident. So the road crews, ambulances etc, know exactly where to stop.

Mechanics of PARP

PARP grabs hold of a simple abundant molecule called NAD, breaks it, and sticks a chunk of it onto the adjacent DNA protein. The important version of this process is the repeating version: this happens over and over, burning through the NAD supply and building up a polymer at the site like some kind of giant flag.
This polymer can be a straight chain. Or it can branch.

Here's a picture of it.

The chemical formula of the branched polymer is made up of 3 components repeated over and over: Ribose sugar, Phosphate, and Adenine.

Unfortunately, our DNA strands are composed of exactly the same 3 components.

Once the polymer gets big, like 100-200 repeating subunits long, the chemistry of it causes the chain to start twisting into a helix.

And once that happens, our cell chemistry makes a fatal mistake.

 

[Robin of Spiritwood]

How it all goes wrong

Remember our Master handyman, Alpha-Synuclein? Doing his job, skating along the helix of DNA looking out for dual breaks?

What happens when it finds a PAR polymer instead, made of the same 3 components, stuck to the DNA at an odd angle, and twisted into a Helix too?

Simple. Alpha-synuclein makes a fatal error.
It thinks it's found a DNA double stranded break.

What does it do? Bind to the PAR polymer instead of the DNA and try to fix it, of course, it's just a dumb molecule, and has only the one trick.

The PAR polymer is normally rapidly broken down by a secondary enzyme called PARG.
PARG cannot degrade the complex with alpha-synuclein- so it goes just before that alpha-synuclein is stuck on, and snips the polymer there instead.

We now have a chunk of alpha-synuclein stuck to a chunk of PAR polymer, that cannot separate. And that, my friends is how we get Lewy Bodies.

Because the freshly snipped cut end of the polymer will just pick up the next alpha-synuclein to come along, and the process repeats till--- all the alpha synuclein is trapped in a spiderweb of complex, there's not enough left to fix REAL double strand breaks, and sooner or later, we get one.

The DNA is now broken, there's Lewy bodies clumping all over the damn place, and the cell stops working.

 

[Yaffle]

Don't forget children there is also DNA in the mitochondria, which can only have come from your mother...

 

[Caramel Clown]

That is a sturdy looking ladder you've got there. It's all I have to say.

 

[Robin of Spiritwood]

HOW TO FIX IT

This I guess is the most important part.

Going to just try to summarize it here: This is proprietary and untested in clinical trials, dosages not worked out, interactions not established, but the biochemistry supports the protocol components individually, and they should be safe at moderate dosages as most of them are just found in food.

Use only at your own risk, after consultation with your well-trained medical expert, who should be experienced in handling the disease. .

I do not reccomend these substances alone or in combination to any patients without explicit request and consent, and in the sole case so far we got side effects within the first couple days consistent with increased endogenous Dopamine production. Specifically nightmares, sleepwalking and hallucinations.
Those effects went away as the old L-Dopa wore off. As you start making more dopamine yourself, it seems the levels can go up too high at first, and it might be better to phase out the L-Dopa completely days before starting new combination treatment.

Mechanic, Substance list.

• Increase NAD, Nicotinamide supplements, Caffeine/Coffee.
• Block NF-Kappa-B, Curcumin/Piperine, Sulphoraphane
• Decoy receptor osteoproteogerin for NF-kappa B, Vitamin D3
• Inhibit PARP enzymes, Minocin/Niacinamide
• Suppress Toll-Like Receptor 4, Sulphoraphane/Curcumin/Fisetin
• Reduce ONOO/H2O2 oxidative stress, N-Acetyl Cysteine, Allopurinol

• Change Gram negative gut flora to drop LPS inflow - Vegan diet, high soluble fibre, MInocin,
• Remove gingival bacterial LPS inflow - Dentist/hygienist
• Chelate out heavy metals and toxins if feasible.

As a rough guide:

• Stop excess DNA breakage, to arrest the pathophysiology.
• Kill off gut bacteria releasing lipopolysaccharides ( LPS)
• Suppress the inflammatory cascade started by the LPS at main mediator NF-KB
• Block the LPS receptor- TLR-4
• Increase the NAD pool by supplying substrate
• Inhibit PARP from making over-big polymers

Below is just some rambling about some components. We do know the following:

• Appendicitis increases the risk
• Coffee and cigarettes are protective
• Toxins like pesticides make it worse
• There are other ataxias caused by Double stranded breaks, as we should expect, like Telangectasia-Ataxia.

Hopefully those will be explained to some degree below.



When we get old, our NAD supply becomes smaller. And we are more susceptible to DNA breaks from accumulated illnesses, oxidation, radiation, and infections.
Additionally, our regulatory enzymes like PARG may slow down, become less efficient. All of that makes Parkinson's possible. The disease starts in the gut, from Bacterial Lipopolysaccharide most likely from gram negative species, travels up via the vagus, and is mediated by Toll-Like Receptor-4 in the target tissues. This can be switched off by hitting an intermediate messenger called MyD88, but again, I don't know how to hit the cascade there.

People who lose their appendixes lose immune function in the gut. Hypothetically, that makes it easier to overgrow the pathological species.

We also need NAD for mitochondrial respiration.
If PARP is ripping along making polymer, our mitochondria will starve and shut down, swell up, and die. The connection between alpha-synuclein is probably incidental: plenty PARP polymer kills off the mitochondria, AND traps the alpha-synuclein, who is still taking blame in 2018.

NAD levels are contingent on a salvage pathway involving 2 other enzymes, NAMPT and NAMAT1. I believe that inhibiting those enzymes would raise the niacinamide substrate level they act on, inhibiting PARP, and fixing the problem better. But I do not know how to hit those enzymes.

Inputting niacinamide is only of limited value, as the enzymes just use it up to make more NAD, and that de-represses the PARP we want to block.

NAD stands for Nicotinamide Adenine Dinucleotide. and yes, we make it out of chemicals that resemble Nicotine. At this point you might be thinking... "CIGARETTES"
And you'd be right.
https://parkinsonsnewstoday.com/201...d-reduced-parkinsons-risk-but-carries-caveat/

If you are a smoker, you have protection against Parkinson's possibly because you took in more nicotine, and made more NAD, and also because Nicotine acts directly on nerve cells as an excitant. But there's a much better way to make your NAD - take a vitamin called niacin, or derivatives like Nicotinamide, Nicotinamide Riboside, or NMN.

NMN is the newest hottest thing to come out of the Harvard labs of Resveratrol man Dr David Sinclair. In case you haven't heard about the Sinclair rats and NMN, you might just want to go look that up.
Here you go:

Source: https://www.youtube.com/watch?v=FxmAeh7mIRk


Any idea why it might be working? Just read the thread. The more NAD we have, the better we can block DNA damage. Duh. That's less of all sorts of bad things, and more energy from mitochondria, plus NAD gets used as a Sirtuin cofactor for acetylation. Anti-ageing, according to Sinclair. .

I can't get those exotic chemicals in the tropics. SO we just used Niacinamide, at a low dosage, which for safety reasons I cannot disclose. People should not copy proprietary research without good results and safety trials.

Niacinamide has another function- it inhibits PARP from making polymer. .That conserves NAD, but more importantly, it reduces the risk of alpha-synuclein capture by giant polymer.
There are other PARP inhibitors available now. Tetracycline antibiotic family works, especially Minocycline.

We can also shunt more raw material into NAD manufacture by making Adenine available.

The chemical formula of Caffeine is very similar to Adenine, and the metabolites of Caffeine will block Adenine breakdown, causing more NAD to form. So, COFFEE.
Does coffee stop Parkinson's?
You bet your butt it does. Nobody knew why. But caffeine works better along with other organic compounds in the coffee.

Of course, we might just skip the preliminaries and try infusing NAD for Parkinson's. Should work.
Has anybody tried it? Well this unsubstantiated testimonial is sure interesting.

Source: https://www.youtube.com/watch?v=g6dNm5WwL7g

 

[Manticore]

Subscribing...thanks Doc.

 

[Robin of Spiritwood]

Just a little update: there's a new clinical trial for both niacin, and nicotinamide in Parkinson's - the " NAPS" trial starting up. So other people are testing the elements of treatment, just without this rationale of the putative underlying mechanism.
They are working from a different perspective, autoimmunity suppression, which I didn't know niacinamide was also involved in.

There is also a Terazocin trial being looked at, from a energy supply perspective, Terazocin induces a glycolytic enzyme, and will fuel mitochondria with more pyruvate. Mitochondria make ATP and that is used to regenerate NAD, so it might work.
The enzyme also increases the function of Heat Shock Protein 90 which is good. This is all fairly new, and might or might not work, looks like a bit of a long shot to me.

I dont want to underrate the energy supply concept. Drugs like Vastarel inhibit mitochondrial functions and make Parkinsons worse, so there's proof that tinkering with the energy pathways can potentially help.