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A\u2010T is characterized by chronic inflammation, neurodegeneration and premature ageing 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\u2010T remains elusive. Here, we utilize human pluripotent stem cell\u2010derived cortical brain organoids to study A\u2010T neuropathology. Mechanistically, we show that the cGAS\u2010STING pathway is required for the recognition of micronuclei and induction of a senescence\u2010associated secretory phenotype (SASP) in A\u2010T olfactory neurosphere\u2010derived cells and brain organoids. We further demonstrate that cGAS and STING inhibition effectively suppresses self\u2010DNA\u2010triggered SASP expression in A\u2010T brain organoids, inhibits astrocyte senescence and neurodegeneration, and ameliorates A\u2010T 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\u2010T and constitutes a novel therapeutic target for treating neuropathology in A\u2010T patients.<\/jats:p>","DOI":"10.1111\/acel.13468","type":"journal-article","created":{"date-parts":[[2021,8,30]],"date-time":"2021-08-30T04:25:46Z","timestamp":1630297546000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":97,"title":["Inhibition of the cGAS\u2010STING pathway ameliorates the premature senescence hallmarks of Ataxia\u2010Telangiectasia brain organoids"],"prefix":"10.1111","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1841-4741","authenticated-orcid":false,"given":"Julio","family":"Aguado","sequence":"first","affiliation":[{"name":"Australian Institute for Bioengineering and Nanotechnology The University of Queensland Saint Lucia Queensland Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harman K.","family":"Chaggar","sequence":"additional","affiliation":[{"name":"Australian Institute for Bioengineering and Nanotechnology The University of Queensland Saint Lucia Queensland Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecilia","family":"G\u00f3mez\u2010Incl\u00e1n","sequence":"additional","affiliation":[{"name":"Australian Institute for Bioengineering and Nanotechnology The University of Queensland Saint Lucia Queensland Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed R.","family":"Shaker","sequence":"additional","affiliation":[{"name":"Australian Institute for Bioengineering and Nanotechnology The University of Queensland Saint Lucia Queensland Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah C.","family":"Leeson","sequence":"additional","affiliation":[{"name":"Australian Institute for Bioengineering and Nanotechnology The University of Queensland Saint Lucia Queensland Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan","family":"Mackay\u2010Sim","sequence":"additional","affiliation":[{"name":"Department of Neurogenetics Kolling Institute Sydney Medical School University of Sydney Sydney New South Wales Australia"},{"name":"Griffith Institute for Drug Discovery Griffith University Nathan Queensland Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2146-6614","authenticated-orcid":false,"given":"Ernst J.","family":"Wolvetang","sequence":"additional","affiliation":[{"name":"Australian Institute for Bioengineering and Nanotechnology The University of Queensland Saint Lucia Queensland Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,8,30]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb2784"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-13018-3"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms6166"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI95145"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri3921"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.251194298"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0543-y"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2233"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkz555"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.12.092"},{"issue":"8","key":"e_1_2_9_12_1","first-page":"1483","article-title":"Abnormal white matter signal in ataxia telangiectasia","volume":"21","author":"Ciemins J. 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