Ann: Appendix 4C & Quarterly Update, page-61

Hi Adreamer, part 2.

C9orf72 gene receptor and ARpolyQ regulate autophagy while their abhorrently expanded isoforms may lead to a failure in autophagy causing an overlapping mechanism which are associated with failure in cell cleaning systems.

https://www.mdpi.com/1422-0067/21/11/4021

Expansion in the C9ORF72 gene are related to significant increase in the bulbar phenotype.

https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2021.700103/full

Unfortunately in the cytoplasm the ARpolyQ protein may block the autophagic flux due to misfolded protein overload. In the case of some MND forms in which autophagy is already enhanced in response to the overload of aberrant aggregation-prone proteins, generic autophagy activators may not be effective treatments.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9704526/

Autophagy and its regulation may considerably differ in the various cell types affected in MNDs (neurons, MNs, glial cells, microglia, muscle cells) making it difficult to identify the proper therapeutic agent for each MND form .

Is Monepantel a generic autophagic drug or does it instead, target the pharmacological factors specifically acting on misfolded protein recognition ? I am on the former at the moment till proven otherwise.

Progressive bulbar palsy is more complex than what most people believe.Finally I believe this study sums up the major difference between bulbar and limb onset MND.

https://www.sciencedirect.com/science/article/pii/S2213158221001182

I did mention a part 3 , it's a personal observation and may have to think a tad more about posting same. It has nothing to do with the effectiveness of MPL, that is a lay down misère in certain conditions.

Kpax