SASP-Secreted MMP-9 from Senescent Microglia Disrupts TDP-43 Nuclear Retention Leading to Cytoplasmic Mislocalization in ALS

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The hypothesis proposes that MMP-9 (matrix metalloproteinase-9), secreted via the senescence-associated secretory phenotype (SASP) from senescent microglia, disrupts TDP-43 nuclear retention by degrading nuclear import machinery components and nuclear envelope proteins, leading to pathological cytoplasmic mislocalization of intact TDP-43 that drives ALS pathology. Rather than directly cleaving TDP