cGAS and STING inhibitors prevent neurodegeneration and premature cellular senescence in patient-derived brain organoids of Ataxia-Telangiectasia.

Ataxia-Telangiectasia (A-T) is a genetic disorder caused by the lack of functional ATM kinase. A-T is characterized by chronic inflammation, neurodegeneration and premature aging features that are associated with increased genome instability, nuclear shape alterations, micronuclei accumulation, neuronal defects and premature entry into cellular senescence. The causal relationship between the detrimental inflammatory signature and the neurological deficiencies of A-T remains elusive. Here we utilise human pluripotent stem cell-derived cortical brain organoids to study A-T neural pathology. Mechanistically, we show that the cGAS-STING pathway is required for the recognition of micronuclei and induction of a senescence-associated secretory phenotype (SASP) in A-T neural cells and brain organoids. We further demonstrate that cGAS and STING inhibition effectively suppresses self-DNA-induced autoimmunity in A-T brain organoids, inhibits astrocyte senescence and neurodegeneration, and ameliorates A-T brain organoid neuropathology. Our study thus reveals that increased cGAS and STING activity is an important contributor to chronic inflammation and premature senescence in the central nervous system of A-T, and constitutes a novel therapeutic target for treating neuropathology in A-T patients.