Anavex Life Sciences Corp (AVXL)

[sokol]

One reason why AVXL 2-73 may be beneficial for PD and AD is this: Sigma 1 agonist, like Cocaine, MAY decrease mTORC1. The author of Anavex Is Likely To Report Positive Parkinson's Disease Trial Results For A2-73, Increasing Share Value https://seekingalpha.com/article/4357368 says this:

"mTORC1 is hyperactive in AD an PD, and hyperactive mTORC1 decreases transcription factor TEFB activity to downregulate autophagy and lysosomal gene expression. And here is the clincher... Cocaine, a sig1R agonist, decreases mTORC1 activity and increases autophagy.

I think it is safe to extrapolate that A2-73 will have the same effect as cocaine since it explains how ULK1 was phosphorylated by A2-73 treatment. In absence of sig1R, autophagosome clearance is impaired, which is exactly what happens in AD and PD. Thus, A2-73 should increase autophagy in AD and PD and this is huge!"

I did a bit of research to better understand and verify the above quote from the Seeking Alpha article. Below are a few of these research references that may help others, like me, that struggle to understand what the author has concluded and whether this one point is valid. I hope to research other points later when time permits. This research may be too basic for some, but helpful for others.


1. ULK1 is an enzyme that in humans is encoded by the ULK1 gene.[5][6]
Unc-51 like autophagy activating kinase (ULK1/2) are two similar isoforms of an enzyme that in humans are encoded by the ULK1/2 genes.[5][6] It is specifically a kinase that is involved with autophagy, particularly in response to amino acid withdrawal. Not many studies have been done comparing the two isoforms, but some differences have been recorded.[7......Ulk1/2 is an important protein in autophagy for mammalian cells....ULK1, specifically, appears to be the most essential for autophagy and is activated under conditions of nutrient deprivation by several upstream signals which is followed by the initiation of autophagy......Ulk1/2 is negatively regulated by mTORC1 activity, which is active during anabolic-type environmental cues. In contrast, Ulk1/2 is activated by AMPK activity from starvation signals.[11]. https://en.wikipedia.org/wiki/ULK1


2.Phosphorylation is important in the fields of biochemistry and molecular biology because it's a key reaction in protein and enzyme function, sugar metabolism, and energy storage and release.....Phosphorylation plays critical roles in the regulation of many cellular processes including cell cycle, growth, apoptosis and signal transduction pathways. Phosphorylation is the most common mechanism of regulating protein function and transmitting signals throughout the cell. https://www.thermofisher.com/us/en/home/life-science/protein-biology/protein-biology-learning-center/protein-biology-resource-library/pierce-protein-methods/phosphorylation.html


3.The mammalian target of rapamycin mTOR complex 1 (mTORC1) negatively regulates autophagic activity via inhibitory phosphorylation of ULK1, and is the key initial regulator of canonical autophagy. More downstream membrane expansion is modulated by two ubiquitin-like conjugation systems (ATG12-ATG5 and ATG8/LC3) and the ATG18 protein family members of WD repeat domain phosphoinositide interacting 1-4 (WIPI1-4), as recently excellently reviewed [10]....it was demonstrated that cocaine-mediated autophagy in astrocytes involves Sig-1R [36].... Sig-1R Activation Induces ULK1 Phosphorylation and Affects Expression Levels of Distinct Autophagy Network Factors Activation of the serine/threonine protein kinase ULK1 (unc-51-like kinase 1) via phosphorylation at serine 555 indicates stimulation of the canonical autophagy pathway. ANAVEX2-73 significantly induced ULK1 serine 555 phosphorylation (up to 2-fold at 1 µM; Figure 2A). Again, we analyzed also PRE-084 as Sig-1R agonist and found that it promotes ULK1 serine 555 phosphorylation to a similar extend (up to 1.5-fold at 1 µM; Figure 2B). It has to be mentioned that this activating ULK1 phosphorylation can be inhibited by mTOR as well as stimulated via AMPK kinase [46], both are basal physiological sensors of nutritional conditions and key signal transducers of canonical autophagy stimulation. ULK1 is actually the signal mediating the induction of the formation of the phagophore during the autophagy process and therefore, a central promoter of autophagy. ULK1 itself functions in a complex with at least three protein partners: FIP200 (focal adhesion kinase family interacting protein of 200 kDa), ATG13, and ATG101. Since a complex pattern of upstream pathways (including mTOR and AMPK) converge on ULK1, it suggests this complex acts as a node converting multiple signals into autophagosome formation https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6468724/)

CONCLUDING COMMENT: OF COURSE, WE MUST WAIT AND SEE THE RESULTS OF ANAVEX TRIALS. IT’S ALL VERY COMPLICATED, AND THE RESEARCH TO BE VALIDATED.