Dear Muneeb Faiq,

to understand more what happens in the neuron as a result of demyelination you first need to know the true function of myelin.

We have "departed" from the evident observation that the mitochondria cannot produce all the ATP needed by the cell and this applies to all cells and, in a very evident way, to the nervous system, which is an obvious paradox because it processes more energy than the other organs but has far less mitochondria. Moved by these energy budgets that did not return, we investigated myelin and discovered that it produces ATP better than mitochondria. So we asked ourselves why he produces it? The most plausible answer was "to support nerve conduction".

In our lab for more than 10 years we have produced hard biochemical evidence that myelin gives an energetic support to the axon and therefore speeds up the CAP. All this because the neuron is very poor in devices that yield energy. So our evidence is for a device (the Myelin) that energizes the neuron and does not isolate it. The strong evidence comes from the experiments of the Nave group (see “Trevisiol…Nave-Hirrlinger J. 2017. Monitoring ATP dynamics in electrically active white matter tracts. eLife 6- DOI: 10.7554/eLife.24241) DOI: 10.7554/eLife.24241 which showed that the firing in myelinated nerve determines the consumption of ATP while the textbooks say that myelin would save energy so…ATP consumption is not allowed ...

We expose this topic rationally in our preprint "The Myelin cannot change the basic mechanisms of axonal conduction.” https://doi.org/10.7287/peerj.preprints.3409v1

I realize that this requires a paradigm shift and I am sorry that international resistance to accepting these changes is enormous. I trust that at least you accept to take these changes into consideration, without prejudice or preconception.

If these premises are accepted, we can then ask ourselves about what happens to the neuron as a result of demyelination. Your sincerely,

Alessandro Morelli - [email protected]

Dear Prof. Morelli,

Thank you for your reply.

As far as I see, your perspective makes sense. I, however, need to do some homework to separate sawdust from iron fillings.

Your ideas are interesting and I am sure they carry a good rationale.

In case, we accept your premise, how would the cells change in demyelination then?

Please give your valuable suggestions.

Regards

Muneeb

And I am curious to know how Myelin produces ATP? It is quite a big chunk of biochemistry though !

Thank you for the credit you give us. It does not happen often ...

1) Why is demyelination happening? I think it's largely due to pollution, especially from lead. You can read our article that I enclose “Impairment of heme synthesis in myelin as potential trigger of multiple sclerosis”.

2) After which the neuron degenerates because it is targeted by free radicals, v. ns. article: “Oxidative stress in myelin sheath: The other face of the extramitochondrial oxidative phosphorylation ability”

3) I add that to have a good myelination it is necessary to drink as much milk as possible with honey both contain galactose, functional to the growth of myelin, v. ns. Article “ Galactose and Hexose 6-Phosphate Dehydrogenase Support the Myelin Metabolic Role.”

Thank you so much if you want to evaluate all this ...

Now I answer your question about the ATP ... one moment...

Your sincerely,

Sandro

I forgott the attachmnt. Now I send to you.

Sandro

In relation to the production of ATP in myelin, yes, it is relly quite a big chunk of biochemistry, however difficult to digest by those who for a lifetime has studied that the mitochondria are (would be ...I told) the “power house” of the cell ...

It simply happens that through the processes of oligodendrocyte the mitochondria migrate and merge with myelin in the process of formation as published by us (see attached). I also enclose an insert of a biochemical text. If you don't give us crazy people, I think we can still hear each other ...

I count on remaining in touch,

Your sincerely,

Sandro

Dear Prof. Morelli,

Thank you for your wonderful perspective and the interesting papers.

I will surely read them.

It will be quite worthwhile to learn novel ideas and may be the Shift of a Paradigm is Somewhere between the lines of your important papers.

I have already written a message to Prof. Panfoli, but I am afraid, due to some busy schedule, she has not been able to write back to me yet.

Best wishes

Muneeb

Dear Prof. Morelli,

I was wondering, if Myelin is so important to neurons, why is it produced by the glia. Doesn't it look like a cunundrum to you?

Look, it's a good question ... I try to give a ontological answer but also (above all) a functional one and, in the end, it is the applied chemical stoichiometry that will tell us if budgets exist that do not return and in those mysterious areas we must go to investigate. Chemistry will not support the needs of dialectics even if expressed by authoritative scientists. Truth wins in science, and it is evident that chemical stoichiometry makes this research more fruitful.

The cell body of the neuron needs a lot of energy and the mitochondria can not provide everything that is needed. However, the mitochondria contained in the cell body are very few and this is just a conundrum: in fact it is paradoxical that a cell that consumes a lot of energy with a request for high oxygen supply for biological combustion has few mitochondria!

Different facts lead us to think that, thanks to the probable fusion of the mitochondria with the Nissl substance (Nissl: the endoplasmic reticulum of the neuron-soma) this gives the soma the “machine” that synthesizes all the ATP it needs but… in the very long axon that happens? The endoplasmic reticulum does not penetrates the axon and it’s true-like that myelin support this energy demand, especially for firing (see " Monitoring ATP dynamics in electrically active white matter tracts” Elife. 2017 - PMID: 28414271) let us not forget, is energetically dispersive. So the white matter, but also the gray matter, energetically supports the axon with myelin. Among other things, there is evidence that neural activity stimulates myelin growth. Keep in mind that the brain has a serious deficit, compared for example to the muscle: it does not possess myoglobin which is slow reserve of oxygen so much that it is extremely affected by ischemia, while for the muscle this criticality does not exist, thanks to myoglobin.

So myelin is home of an active energy metabolism with aerobic degradation of glucose, which, through the Krebs cycle - which we have shown to be very active in myelin (see our article “Tricarboxylic acid cycle-sustained oxidative phosphorylation in isolated myelin vesicles” PMID: 23851157), supports "outside" the neuron's energy needs, above all to support firing.

But there's more!

In fact, for go on the combustion the myelin need a lot of oxygen and that's why the myelin has the highest content of carbonic anhydrase (CA) of the whole organism. Let us remember that CA is the enzyme that combines the carbon dioxide produced in gaseous form with water to make it soluble in the form of bicarbonate. Remember us that if the CO2 remained gaseous (let's remember that in this state it is produced by the Krebs cycle) in the brain we would have terrible seizures! Furthermore, again to be in the subject of oxygen, myelin dissolves oxygen quite well and therefore constitutes a slow reserve of oxygen to support neuronal combustion, even if it is not as efficient as myoglobin. In fact, white matter resists better the hypoxia of gray matter.

So many data would then remain mysterious if we do not take into consideration the chemical reactions we have now mentioned are operative in myelin.

At last to answer with the ontological profile, I hope that I have answered your question, and we can realize that all this chemical support to the axon from myelin could not be supported by the neuronal cell alone. I believe that it is possible to look at the issue from a teleological point of view, but if we talk about it we will talk about it another time…

Yours sincerely,

Sandro