Glial fibrillary acidic protein

[Wishful]

I came across an article about markers for the results of brain surgery. One of the terms was "Glial fibrillary acidic protein. Looking it up, I found that it's important for glial function; without the protein, astrocytes won't connect to neurons, and I suppose that even small changes in level will affect brain function. The article did mention fatigue as a possible result of changes in this protein. A search for this protein and ME/CFS didn't find any links. I think this would be a good candidate for ME/CFS research.

This protein is also used in growing/maintaining skin, hair, cartilage and bone, and the lining of the brain and spinal cord, and liver and pancreas. I've seen complaints about ME affecting all those areas, so this could be a common link. Maybe a small change in expression of that protein, caused by cytokines affecting astrocytes, would create the neurological symptoms (via astrocytes), and also possibly show up as symptoms in those other areas.

Maybe some researcher reading this will think it's worth at least considering.

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[Osaca]

Could you provide more information on why exactly this would be a good target for research and not something else? I’ve just had a very quick look and had never heard of GFAP before and these are my questions/findings.

Are there any recordings of GFAP gene mutations relevant to ME/CFS or why would very specific viruses cause it’s decay or alteration (predominantly thinks like Herpesviruses and SARS)? Apparently GFAP can decrease due to a viral infection or because of a neurodegenerative disease https://www.nature.com/articles/4000696. One of these viruses is for example VZV https://zenodo.org/record/1229976 and it is known for acute Covid as well as there are quite a few studies on this https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9212259/, https://alz-journals.onlinelibrary.wiley.com/doi/pdf/10.1002/alz.12556 https://academic.oup.com/brain/article/145/7/2555/6621999. However, a normalisation seems to take place https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8320425/ even though some of these patients still had Long-Covid symtoms including fatigue and brain fog. This seems to be quite a significant finding in this context. Shouldn’t we have noticed somehow elevated or decreased findings in ME/CFS (at least for Long-Covid this has at least been measured when studying neurodegenartion and some studies also suggested https://www.frontiersin.org/articles/10.3389/fmed.2023.1085988/full it should be measured, especially since it was measured for acute Covid)?

What about other related proteins would vimentin, peripherin, desmin or maybe other things that can interact with GFAP be disturbed in someway? If it interacts with things like MEN1, PSEN1 or whatever else there is, wouldn’t these things have come up in a study? It seems GFAP staining is quite easy (or at least not as hard as many other things), surely there must have been ME/CFS patients that also had some sort of brain injury or even a tumor?

There’s actually an autoimmune disease called Autoimmune GFAP astrocytopathy, which was only recently discovered https://jamanetwork.com/journals/jamaneurology/fullarticle/2548268. However, its symptoms look very different from ME/CFS and are measurable by biomarkers as well. But that at least means that these things are sometimes looked for. There’s actually a single case report for a reactivated EBV causing Autoimmune GFAP Astrocytopathy https://onlinelibrary.wiley.com/doi/abs/10.1111/cen3.12659, however this patient did have positive EBV in the CSF and of course Anti-GFAP antibodies as well. Possibly more importantly though PEM doesn’t seem to be associated to this disease.

Maybe this is even something the intramural study had a look at? It did go quite deep and did things like metabolic studies on neurons made from patient blood stem cells, so this doesn't seem out of its reach? The intramural study also did extensive mice studies. At the same time, just glancing over the GFAP research, mice studies with GFAP seem to give quite strong results, so maybe with some luck this could be the case here as well?

Of course there are far more diseases somehow also related to GFAP like Alexander’s disease and even MS patients seem to have elevated levels in blood serum etc. Interestingly there's also a fibrinogen connection https://www.cell.com/neuron/pdf/S0896-6273(22)00910-2.pdf. As always far more is unknown than known.

The key question a researcher might ask is why should the limited resources be invested here and not say in EBV reactivation or cytokines affecting astrocytes, which could cause these GFAP changes, if they even exist? Or why not try to did deeper into the microglial and astrocytes problems directly, after all it seems like the results by Nakatomi et al. are still largely unreproduced https://pubmed.ncbi.nlm.nih.gov/24665088/.

According to Herbert-Renz Polster GFAP is still understudied in ME/CFS https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9124899/, so at least it seems that some work should still be done and that there's awareness for this topic, but he also mentions that "GFAP values may not reflect neuroglial dysfunction in the absence of cellular disintegration (as seen in multiple sclerosis or traumatic brain injury)". I'm sure van Elzakker knows all the ins and outs. As always limited funding is probably the issue. A reasonable approach around this is probably to first try to get grants for Covid/Long-Covid and then try to extend these grants or do some research on the same topic, but for ME/CFS on the side.

 

[vision blue]

@Wishful

 

[Wishful]

Could you provide more information on why exactly this would be a good target for research and not something else?

You answered that in the following sentence: "I’ve just had a very quick look and had never heard of GFAP before". This was my first encounter with the term, and it sounded like something that could explain ME (structural problems in glia), and it's something probably hard to study in living brains (thus hasn't been noticed yet), and at least a quick check didn't show that it had been considered WRT ME, so to me that makes it a candidate for at least consideration for study. Maybe some expert will consider it and judge that it's unlikely, and thus low priority for study. However, maybe someone else will consider it and decide that it fits their observations or theories quite well.

If GFAP has been studied, has it been studies properly? A check for amounts in serum might be useful for some disorders, but it might not reveal highly localized dysfunction. It sounds like an important structural element in glia, so what if the molecules are forming improperly? The changes might be difficult to notice if you're not specifically looking for them, but they could make the difference between thinking clearly or being brainfogged, or having various other effects of parts of the brain not working quite right.

I'm certainly not the one to judge where research resources should go, but to me this sounds like something that should at least be on the list of things to consider.

BTW, thank you for the link at the end. I haven't done a search for latest ME research for a while, but that paper fits my thinking of ME: that it's a neuroglial disorder.

 

[Wishful]

How is GFA protein produced?

I'm no expert on it, but from the Wiki page, it implies that it's produced in the cells where it's used, and different forms may be produced in different types of cells (brain, skin, etc).

As for treatment, I doubt that it's a simple deficiency, solved by swallowing a pill. It could be something like a different isoform being created in the presence of certain cytokines or in altered localized ratios of nutrients. I think it would be very difficult to intentionally "fix" a localized GFAP problem. I suppose that is the kind of disorder that would result in different individuals getting benefits from surprise treatments, which don't work for anyone else.

 

[vision blue]

@Wishful
I dontbknow enuf ablut it obviously. Sometimes one can tweak genes and get them to up regulate pro teins but if with different isoforms this also implies different splicing then its just too complicated.

The different places producingbown supply not incommon but sometimes one useful thing is any bottlenrcks or pathway issues in one site may well be found in all sites. So means someone may be more easily able to test for it in an accessible site like the skin and any problems there may well be mirrored in its brain production too, even if the latter cannot be easily measured itself

 

[vision blue]

gg