TBK1 Loss Triggers eIF2α-Mediated Translational Repression Through Microglial SASP-Induced Integrated Stress Response in Motor Neurons

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This hypothesis proposes that TBK1 loss-of-function mutations drive ALS pathogenesis through a two-step mechanism: first, TBK1-deficient microglia adopt a senescent state and release SASP factors (TNF-α, IL-1β, type I interferons) that act as paracrine stressors on motor neurons; second, these inflammatory signals chronically activate the Integrated Stress Response (ISR) in motor neurons, leading