Inactivation of ATG13 stimulates chronic demyelinating pathologies in muscle‑serving nerves and spinal cord, 2025, Drosen et al.

I seem to remember an effort to put together a minimum set of phenomena that any hypothesis must explain, lead by @rvallee? Maybe this is a good test case to test that list.

I'm yet to read the paper, but there are several things that doesn't sound right to me and already pointed out by others (inflammation, demyelination...). But it also posits the activation of microglial cells which could explain a lot of things in ME/CFS. I suppose the rapamycin study at Simmaron will tell us if the hypothesis is in the right path.
 
In economics we say "all models are wrong, some are useful".

It remains to be seen if this is one of the useful ones, but I very much appreciate the idea of developing animal models: it's how you get high-throughput science.

I've often wondered if we could simply try to generate murine mecfs in the old-fashoned way. Taking mice and trying different infection combinations on them: ebv then covid; hhv6 then enterovirus; etc. Exercise them and see if any percentage never seem to recover. Repeat until you find the precise combination of timing and infection and predisposition that creates mecfs predictably. And then feed those mice into a drug testing pipeline! Perhaps there's a great reason this hasn't been tried.
 
as for myelin, there was a Stanford paper last year that hinted indirectly at dymyelination:
Abstract
Here we report preliminary data demonstrating that some patients with myalgic encephalomyelitis/chronic fatiguesyndrome (ME/CFS) may have catalytic autoantibodies that cause the breakdown of myelin basic protein (MBP). We propose that these MBP-degradative antibodies are important to the pathophysiology of ME/CFS, particularly in the occurrence of white matter disease/demyelination. This is supported by magnetic resonance imagining studies that show these findings in patients with ME/CFS and could explain symptoms of nerve pain and muscle weakness. In this work, we performed a series of experiments on patient plasma samples where we isolated and characterized substrate-specific antibodies that digest MBP. We also tested glatiramer acetate (copaxone), an FDA approved immunomodulator to treat multiple sclerosis, and found that it inhibits ME/CFS antibody digestion of MBP.
https://www.s4me.info/threads/catal...tigue-syndrome-2023-jensen-davis-et-al.36338/
 
Murph said:
Perhaps there's a great reason this hasn't been tried.
Click to expand...

It wouldn't be high throughput. I doubt it could ever be predictable and reliable*. Arguably it's cruel.

I think there's much more scope in human studies (in well characterised ME/CFS cohorts): peripheral blood, urine, sputum, CSF, tissue (esp muscle biopsies) and non-invasive imaging.

* It might only take effect if there's a stochastic infection into a specific marrow precursor cell.
 
Fingers crossed that this all leads to something, but since a lot of cell biology is controlled by TOR signalling in the broad sense (possibly everything in the cell will be affected by changes to it - and probably in every type of cell) one would expect to see disease of some kind manifest when stuffing with it. Proving how ME-specific the illness outcome in the animal model is will be the crucial thing I think. Wishing the team good luck in this ambitious line of investigation.
 
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