TBK1 Loss Drives Microglial Senescence-SASP to Generate MMP-9-Mediated TDP-43 C-Terminal Fragments in ALS

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This hypothesis proposes that TBK1 loss-of-function mutations initiate a pathological cascade where microglia become locked in a senescent state, secreting MMP-9 via the senescence-associated secretory phenotype (SASP), which then generates pathological TDP-43 C-terminal fragments that propagate ALS pathology. The mechanism begins with TBK1 haploinsufficiency disrupting normal microglial homeostas