Hi Kpax,
This is interesting and it definitely caught my attention so much so that I have spent significant time on this and had to check in with a Dr friend of mine to help me appreciate this one. Very interesting find.
What was pointed out to me was that SBMA is caused by a defective androgen receptor containing an elongated polyglutamine tract and that there is no direct link between ARpolyQ toxicity and bulbar onset ALS, or more broadly, ALS based on available search (that we could find)
https://pubmed.ncbi.nlm.nih.gov/16781019/I don't know if you have a paper that did provide direct linking ??
It has been reported in NSC34 cells that ARpolyQ aggregates were sent to the proteasome for degradation as a compensatory mechanism when autophagy was inhibited/blocked, which implies that autophagy might not be strictly needed to clear aggregates, but this was again in the context of SBMA, (and only in a cell line) and not bulbar onset ALS.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3748343/I reviewed our trial inclusion/exclusion criteria >
https://classic.clinicaltrials.gov/ct2/show/NCT04894240?term=Monepantel&cntry=AU&draw=2&rank=1I think the SOD1 exclusion is interesting>
Patients at risk of or known to carry a SOD1 mutation or VCP mutationThere was some risk of toxicity as far as I can ascertain regarding SOD1 > SOD1 is also understood to modify TDP43, and therefore on the toxicity front, this paper says TDP43 may be involved in motor neuron death in SOD1 fALS.
https://pubmed.ncbi.nlm.nih.gov/29982983/I also found this which was very interesting: The pathology of SOD1 ALS seems distinct from that of all other types of ALS, in that it lacks the TDP-43 and/or FUS pathology hallmarks and may explain further its exclusion:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8902152/VCP I found this: Valosin Containing Protein (VCP) was one of the first genes associated with both Frontotemporal Dementia (FTD) and ALS representing an early example of gene overlapping and on how its mutations are linked to the neuropathology.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8902152/I am still trying to figure out VCP (still reading)... Don't know if you can get to the bottom of this one.
....
All up, I am not so convinced that MPL and its mechanisum of action won't work on bulbar based on what i have found but hey.. as I mentioned earlier, I reckon there is so little known on MPL (and mTOR in general) and ALS/MND it is like a thimble of water in an ocean
adreamer.
(20min delay)