TBK1 Loss Triggers eIF2α-Mediated Translational Repression Through Microglial S…

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 to pathological eIF2α phosphorylation and catastrophic repression of axonal protein synthesis. The mechanistic cascade begins with TBK1 haploinsufficiency disrupting microglial autophagy and NF-κB/IRF3 signaling, trapping microglia in an aged transcriptional state. The resulting SASP cytokines activate PKR and PERK kinases in neighboring motor neurons, elevating eIF2α phosphorylation from the normal 0.3-0.5 range to pathological levels of 0.7-0.9. This ISR overflow causes >70% reduction in synthesis of critical axonal and synaptic proteins (SNAP25, SYN1, VAMP1), leading to NMJ denervation and motor neuron death. The model predicts that TBK1-mutant ALS patients will show elevated microglial inflammatory signatures coupled with motor neuron ISR activation markers (ATF4, CHOP upregulation). Therapeutic intervention would require dual targeting: restoring TBK1-dependent microglial homeostasis (potentially through autophagy enhancers or anti-SASP compounds) and selective ISR modulation in motor neurons using eIF2α phosphatase activators like sal003. This explains why TBK1 mutations cause both familial ALS and the characteristic motor neuron-selective vulnerability, as the microglial SASP creates a neuron-autonomous translational crisis specifically in metabolically demanding motor neurons.