TBK1 deficiency in microglia creates a pathological cascade that directly generates ALS-driving TDP-43 pathology through senescence-associated secretory phenotype (SASP) mechanisms. When TBK1 is lost or mutated, microglia become locked in a senescent state characterized by dysregulated NF-κB and IRF3 signaling, defective p62-mediated autophagy, and chronic cGAS-STING pathway activation. This senescent microglial state produces a toxic SASP cocktail enriched in matrix metalloproteinase-9 (MMP-9), which is secreted into the extracellular space and taken up by neighboring neurons. Once internalized, MMP-9 acts as a pathological protease that cleaves full-length TDP-43 protein at specific C-terminal sites, generating neurotoxic 25kDa and 35kDa fragments. These aberrant TDP-43 fragments cannot properly shuttle between nucleus and cytoplasm, instead accumulating in cytoplasmic inclusions that serve as pathological seeds for further TDP-43 aggregation. The fragmented TDP-43 species exhibit enhanced prion-like properties, propagating from cell to cell and recruiting normal TDP-43 into insoluble aggregates.

TBK1 deficiency in microglia creates a pathological cascade that directly generates ALS-driving TDP-43 pathology through senescence-associated secretory phenotype (SASP) mechanisms. When TBK1 is lost or mutated, microglia become locked in a senescent state characterized by dysregulated NF-κB and IRF3 signaling, defective p62-mediated autophagy, and chronic cGAS-STING pathway activation. This senescent microglial state produces a toxic SASP cocktail enriched in matrix metalloproteinase-9 (MMP-9), which is secreted into the extracellular space and taken up by neighboring neurons. Once internalized, MMP-9 acts as a pathological protease that cleaves full-length TDP-43 protein at specific C-terminal sites, generating neurotoxic 25kDa and 35kDa fragments. These aberrant TDP-43 fragments cannot properly shuttle between nucleus and cytoplasm, instead accumulating in cytoplasmic inclusions that serve as pathological seeds for further TDP-43 aggregation. The fragmented TDP-43 species exhibit enhanced prion-like properties, propagating from cell to cell and recruiting normal TDP-43 into insoluble aggregates. This creates a self-amplifying cycle where TBK1-deficient senescent microglia continuously secrete MMP-9, generating more pathological TDP-43 fragments that spread throughout neural networks. The mechanism explains how TBK1 mutations cause ALS through a non-cell-autonomous pathway: the primary defect occurs in microglia, but the pathological consequence manifests as neuronal TDP-43 proteinopathy. This hypothesis predicts that MMP-9 inhibition or senolytic therapies targeting senescent microglia could interrupt the TBK1→MMP-9→TDP-43 fragmentation axis.