The Rhyothemis princeps Brain Externalization Project

Yesterday I watched two introductory videos on the ubiquitin-proteasome system - very important in autoimmunity, aging, cancer and neurodegeneration. Alfred Goldberg, Functions of the proteasome, R&D Systems,  recorded February 4, 2016:  Index: 9:30 start of presentation 13:20 ubiquitin-proteasome pathway summary slide - ATP required 15:22 antigen presentation - 1% of product peptides are taken up by ER and displayed in cell surface by MHC class I molecules - proteasome allows immune system to screen intracellular space for abnormal proteins (pathogen or cancer) 23:16 multiple ATP dependent steps in proteasome function 38:00 Bortezmib - proteasome inhibitor, inhibits NF-kB, does not cross BBB, induces apoptosis 40:33 Endoplasmic-reticulum-associated protein degradation (ERAD) pathway is unusually activated in multiple myeloma cells ; proteasome inhibition results in increased ER stress and triggers UPR, further UPR activation triggers apoptosis 42:30 proteasome inhib

Mutations in the gene that codes for LRRK2, a kinase, are a risk factor for Parkinson's disease . Increase in the kinase activity of LRRK2 caused by these mutations leads to increased apoptosis and neuronal loss in PD.   Vitamin B12 inhibits LRRK2 kinase activity: https://pubmed.ncbi.nlm.nih.gov/21198553/   "Herein we identify 5'-deoxyadenosylcobalamin (AdoCbl), a physiological form of the essential micronutrient vitamin B 12 as a mixed-type allosteric inhibitor of LRRK2 kinase activity. Multiple assays show that AdoCbl directly binds LRRK2, leading to the alterations of protein conformation and ATP binding in LRRK2. ... Our study uncovers vitamin B 12 as a novel class of LRRK2 kinase modulator with a distinct mechanism, which can be harnessed to develop new LRRK2-based PD therapeutics in the future. "   High B12 status has been found to be associated with increased  risk of lung cancer: "Circulating concentrations of vitamin B12, based on pre-diagnos

Last notes were about intracellular pH and senescent cell clearance, cancer and neurodegeneration. Just a few days later, an article on Nrf2 appeared in my news feed: https://medicalxpress.com/news/2021-01-nrf2-magic-molecule-eternal-youth.html "At the risk of overstating the obvious, if a little extra NRF2 is good for every cell in your body, and every cell in your body is good, then NRF2 must be good for your body. The weak link in that argument, however, is that all cells are not good. Nobody wants harmful bacterial cells to flourish, and nobody wants cancer cells to flourish. A paper recently published in Nature now suggests that inhibiting NRF2 can block the migration and invasion of non-small-cell lung cancer cells through the body. If anyone is going to derive benefit from NRF2, they may need to be smart about it. The main reason NRF2, or Nuclear factor-erythroid 2-related factor 2, is so highly sought, is because it is a key transcriptional regulator of several an

New article on kidney type glutaminase and senescent cell clearance: https://science.sciencemag.org/content/371/6526/265   related:   Simultaneously Targeting Tissue Transglutaminase and Kidney Type Glutaminase Sensitizes Cancer Cells to Acid Toxicity and Offers New Opportunities for Therapeutic Intervention https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4291776/   It's interesting that this all hinges on intracellular pH; there was a good talk on intracellular pH and neurodegeneration a while back: https://youtu.be/OUmFkfTFm_o