eIF2α Phosphorylation Imbalance Disrupts Mitochondrial Protein Import and Bioenergetics in ALS Motor Neurons

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The Integrated Stress Response (ISR) controls cellular protein synthesis through eIF2α phosphorylation, but this hypothesis proposes that chronic ISR activation in ALS motor neurons creates a pathological cascade that specifically disrupts mitochondrial protein homeostasis and bioenergetics. In ALS, chronic eIF2α~P elevation (>0.7 normalized phosphorylation) caused by proteostatic stress from TDP-