ALS lesson for today.
This is how ALS works:
In the rough endoplasmic reticulum (RER), just outside the nucleus, eIF2 (eukaryotic translation initiation factor) brings Met-tRNAi (Initiator Methionine tRNA) to the ribosome as the eIF2-GTP•Met-tRNAi ternary complex. Met-tRNAi Functions in Directing the Scanning Ribosome to the Start Site of Translation, and the ribosomes translate RNA into proteins that are then folded.If that folding goes wrong, for example because of a DNA mutation, a translation error, too much or too little of some chemicals or chemicals replacing amino acids, (partly)unfolded proteins remain in the RER. The RER then gives off a stress signal.
BiP (Binding immunoglobulin protein) works as a sensor of unfolded proteins in the ER and regulates the activation of these ER stress transducers. Under normal conditions, BiP binds to the lumenal domains of Ire1α, Ire1β and PERK (Eukaryotic translation initiation factor 2-alpha kinase 3), and prevents their homodimerization transport to the Golgi apparatus. Under ER stress conditions, BiP binds to unfolded proteins and thereby renders each transducer to activate.
PERK phosphorylates eIF2, which blocks the binding of the initiator Met-tRNA to the ribosome leading to its inactivation, and thus to a rapid reduction of translational initiation and repression of global protein synthesis. This is called the unfolded protein response (UPR).
This reaction can temporarily be beneficial, but if the ER stress is prolonged and severe, the UPR can result in cell death through the activation of multiple apoptotic signaling cascades, including CHOP (the CCAAT/enhancer-binding protein homologous protein), also known as GADD153-mediated pathway (growth arrest and DNA damage gene 153), TRAF2 (IRE1/tumor necrosis factor receptor-associated factor 2-mediated pathway), and Ca2+-dependent pathway.
You do need some knowledge of cell organelles and biochemistry to understand this, but I can't make it any simpler.