eIF2α Phosphorylation Imbalance Creates Integrated Stress Response Overflow That Represses Axonal Protein Synthesis in ALS

h-alsmnd-870c6115d68c

The Integrated Stress Response (ISR) is a central regulatory pathway that controls global protein synthesis through phosphorylation of eIF2α (Ser51). In ALS motor neurons, this hypothesis proposes that chronic ISR activation (via PERK, GCN2, HRI, or PKR pathways) caused by proteostatic stress (TDP-43/FUS aggregates), oxidative stress, and ER stress creates a pathological eIF2α~P state that repress