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The molecular mechanisms of toxicity associated with cytoplasmic accumulation of TAR DNA binding protein-43(TDP-43),a pathological feature of many neurodegenerative diseases,are not fully understood.A recent study by Yu et al.is proposing that noxious neuroinflammatory stimulation associated with TDP-43 pathology is caused by excess TDP-43 penetration into mitochondria followed by cytosolic release of mitochondrial DNA(mtDNA)and activation of the cGAS/STING immune sensor.