SASP-Secreted MMP-9 from Senescent Microglia Disrupts Nuclear-Cytoplasmic Trans…

This hypothesis proposes that MMP-9 secreted by senescent microglia in the SASP drives ALS pathology through disruption of nuclear-cytoplasmic transport rather than direct proteolytic cleavage of TDP-43. MMP-9 degrades components of the nuclear pore complex, particularly nucleoporins such as NUP62 and NUP88, which are essential for maintaining the nuclear-cytoplasmic transport machinery. This proteolytic degradation compromises the nuclear import of TDP-43, leading to its aberrant cytoplasmic accumulation and subsequent aggregation. The disrupted transport also impairs the nuclear export of mRNAs that TDP-43 normally regulates, creating a feed-forward loop of RNA metabolism dysfunction. Cytoplasmic TDP-43, now separated from its nuclear targets and present at abnormally high concentrations, undergoes phase separation into pathological aggregates that sequester RNA-binding proteins and disrupt local protein synthesis. These aggregates serve as seeds for prion-like propagation to neighboring neurons through extracellular vesicles or direct cell-to-cell contact. The senescent microglial SASP creates a tissue environment rich in inflammatory cytokines that further compromises nuclear integrity and promotes the spread of transport dysfunction. This mechanism explains the progressive nature of ALS pathology and suggests that therapeutic interventions targeting nuclear pore integrity, MMP-9 activity, or microglial senescence could prevent the initial trigger of TDP-43 mislocalization and subsequent neurodegeneration.