Do not trade this blog as 4 billion years of evolution is against me and possibly even God laughs at it, He has a great sense of humor!
When neuron become strassed, like in inflammation or infection, they produce proteins in respnse. In order to produce protein they need to read the right part of their DNA, and then transcribe that into messengerRNA. Then mRNA is used to create chain of amino-acids (translation) which then is folded into functional protein by chaperone protein (folding). If these proteins are not folded correctely by chaperone proteins than they are forming aggregates like Amyloid Plaque or Tau in Alzheimer’s. It seems that different proteins are resposible for different CNS diseases, or rather their misfolded version building up into aggregates. The researchers were looking at Hutington’s and ALS proteins. Altogether they looked at 66 chaperones proteins, and found out that some of them made things even worse for the cells and some cured the cells completely.
Here, I would like to add that this paradigm is able to explaine the dichotomy of familial and sporadic disease. The familiar arise due to geneic fault to needed protein but the sporadic form of the disease is caused by wrong choice of the chaperone needed to address the need to properly fold the protein.
Regarding the SIGMAR1 gene/protein. SIGMAR1 agonist is used to by private Isreali company called Prilenia to cure Huntington’s. I have also learned that a form of familiar form of ALS involves genetic defects to the SIGMAR1 protein. This suggests that SIGMAR1 protein and the agonist are directly related to this discovery.
Unfortunately, the group found, this is where the bottleneck lies. In cells with Huntigton-associated protein aggregates, ]the cells sensed there was a problem, and activated some stress-response chaperones, but not the correct ones. The cells did not know what was causing the stress, or what they should do to correct the situation. With ALS-associated aggregates, things were even worse; the cells did not realized that they needed to activate chaperones at all and displayed no signs of stress.
We know that SIGMAR1 agonist release large number of proteins from Mitochodria Associated Membranes which could be a blanket resonse to the stress experienced by the cells. Also, it seems the agonists work by correcting or acting on the reading of the DNA, the transcription process in the nucleaus, which might suggest that the right chaperones are going to be transcribed and translated by the cells in order to address the stress caused by build up of aggregates. The clinical studies so far done by $AVXL point to early intervention in large number of CNS disease, being both neurodegeneraive and neurodevelopmental, to be most effective. This suggests natural homeostasis regulation before the cellular physiology becomes proverbial train-wreck. The scientific body of work point to dual function in both trascription from DNA to translation, or rather folding of proteins. The broad range of involvments of SIGMAR1 in cellular physiology suggests that some very basic repair mechanism can be put in action with the drugs.
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