Long Non Coding RNAs and pain

I heard a talk today about people who cannot feel pain. Some of them have genetic defects in genes that do not produce proteins but produce Long Non Coding RNAs. These seem very interesting.

A gene 'normally' is a piece of DNA that can be copied to RNA which is then read off by a ribosome to make a protein. LNCRNA genes are copied to make long bits of RNA that bind back on DNA elsewhere to regulate other genes. There aren't many of these in simple organisms but there are lots in complex organisms like us. They are involved in telling specific types of cell to do specialised things.

If ME/CFS or fibromyalgia was due to a genetic defect in one of these genes a GWAS screen should pick it up, if the right SNPs are looked for. But you might well see nothing on proteomics. Since ME/CFS is not present at birth it might be more likely that it involved some disordered expression of one of these genes rather than a genetic DNA defect. The interesting thing there would be that over or under expression of one of these genes in nerve cells relating to fatigue or pain perception would probably be completely invisible on any known tests.

It struck me that it would be a good example of a mechanism that had not been found simply because we do not know how to find it.

 

Are there no transcriptomics tests that could sequence these?

Edit: Oh because if it was nerve cells it'd be hard to study them, I assume.

 

So possibly a complex disordered expression of certain genes, for which the likelihood of an overexpression in certain cells taking place somehow increases after certain events have occured (say an infection or a certain age has been reached) but where there is also a (smaller) possibility of returning back to the old steady state?

 

I know this is probably unanswerable but could a mechanism like this be responsible for treatment resistant nerve related pain with current pharmaceutics in ME?

Nothing has helped my widespread pain and I’ve taken the majority of what’s available these days for neuropathic pain. In fact many things that act on the nervous system paradoxically make my pain worse.

 

So a GWAS wouldn't pick it up if it was due to disordered expression rather than defect? A fascinating and horrifying thought. If there are no tests, is there any way to probe this hypothesis further.

Hypothetically (ignoring the ethical concerns) could a drug be developed to target these genes and then given to patients to see if they improve?

 

I don’t know anything about GWAS, but I do know that a lot is happening in AI. And AI is really, really good at spotting patterns in data. So it has never been more likely that we would be able to find something if it actually existed.

I hope that DecodeME makes the data publicly available. If they do, we might want to try and lobby Google to get them to have a go at it. AlphaFold was thought to be impossible.

 

I think it would be a good candidate.

 

I'm unclear what the difference would be between fatigue and pain, and the perception of fatigue and pain, but the potential genetic role is intriguing. Of course, with ME/CFS it only seems appropriate that we wouldn't be able to demonstrate that role conclusively.

 

What they do with the lab rats is get them dead, take out the dorsal root ganglia and do immunofluorescence on tissue sections! One could conceivably do that with an ME/CFS 'PM tissue bank' but getting standardisation with controls would be a nightmare.

Yes, that is the claim this group is making - that these genes could be targeted with pharmacological agents.

The question is how you identify the right gene target. That might become clear for other reasons though.

The interesting thing to me is that this sort of pathway could explain why it is so difficult to find anything. The pain insensitivity syndromes were not found for a long time because there is no protein made by the genes - now they know how to find such genes and what they do.

 

I was not referring to the perception of fatigue and pain but the processes of fatigue and pain perception (or the processes via which fatigue and pain are generated), which will be a complex multistep affair involving receptors, nerve fibres, nerve cell bodies, synapses, more nerve fibres, more cell bodies, more synapses... And the end result will be pain or fatigue. The error in the perception process is at different points in different people.

 

Ok, but I'm still unclear of what you're trying to say. I get that you need eyeballs to see, and neurons, etc, but it's still redundant to say the perception of seeing. And why assume there is an error in the perception process? If you assume that because, say, we can't find any overt structural damage in pwME, aren't you running the risk of not looking under a different lamp post?

Hey, you may be right. I just find it a worrisome theory to embrace.

 

Does that mean nothing would show up in DecodeME?

 

As far as I understand, In Jonathan’s thought experiment imagining a “disordered expression”, no.

Though we could assume there might be genes more associated with that disordered expression happening in the first place so they might give weak signals in the GWAS.

 

It could be worth pursuing then, even if tricky. Hard to get funding without more evidence though I'd imagine.

Interesting, can you say more about this?

 

It is not just redundant but meaningless.

The term used is visual perception.
As for auditory perception.
Or pain perception.

Science is about getting the right answer, not about theories being 'worrisome' (for whatever reason). Only the right answer will lead to successful treatment.

 

Why would it be a nightmare?

 

Involvement of these genes does not make DecodeME any more or less likely to find something. DecodeME will only pick out genetic predispositions. It will not pick out shifts in gene expression later in life - but that applies to any acquired disease. If LNCRNAs were involved in pain perception in ME/CFS there still might be a signal on DecodeME for a variant of one of these genes that is more susceptible to disordered expression or a completely different gene that controls the LNCRNA gene in some way. That could even be something like complement factor H.

 

For immunofluorescent experiments you really need to line up a set of test samples from patients and a set of control samples and stain them all in the same 'run' - i.e. at the same time on a certain day - because the quality of the reagent may change with lab temperature or time in the fridge or whatever.

To gather enough samples to give a statistically useful result you would probably need to freeze down at least ten patients' tissues at -80°C and a similar number of samples from people dying in car accidents, all of which would need consent, a dedicated storage bank and all the admin of running that bank for maybe 5 years until you had enough samples.

Since almost no post-mortems are done nowadays you would also need a dedicated neuropathologist to agree to take the samples fresh for you, travelling to whatever hospital the person died in.

I could go on, but it ain't simple.

 

In theory only. And when it comes to medicine, pretty much for the idealogues only. In reality, particularly when you stray into contested disease territory, science can have little to do with getting the right answer. I know you know this. It may just as easily blur into the background with the noise from politics and industry and legacy concerns.

That observation does not undo the merit in the faulty gene expression theory.

 

Wasn't there a mouse model for ME/CFS? Or is it not valid? What if "something in the blood" successfully replicates previous results? Maybe we can induce ME/CFS in rats somehow, take healthy control rats and do immunofluorescent experiments.

How did they get "unhealthy" rats for their experiments?