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Tubers are thought to result from somatic second-hit mutations that disrupt the\n                    <jats:italic>TSC1<\/jats:italic>\n                    or\n                    <jats:italic>TSC2<\/jats:italic>\n                    genes in neural progenitor cells, driving hyperactive mTORC1 signalling\n                    <jats:sup>2<\/jats:sup>\n                    . Glial abnormalities are commonly observed in tubers\n                    <jats:sup>3<\/jats:sup>\n                    ; however, whether glia actively cause disease or merely result from chronic seizure activity has remained unclear. To address this question, we used human brain organoid models to track the developmental fate of mutated progenitor cells in the absence of seizures. Here we show, using single-cell transcriptomics and cyclic immunostaining across human brain organoids and resected tuber tissue from patients, that loss of TSC2 biases neural progenitors to differentiate into enlarged, pro-inflammatory reactive astrocytes in a cell autonomous manner. These mutant astrocytes show downregulated glutamate transporter expression, increased inflammatory cytokine secretion and elevated expression of neurodegenerative disease risk genes such as\n                    <jats:italic>APOE<\/jats:italic>\n                    and\n                    <jats:italic>CLU<\/jats:italic>\n                    . Our findings demonstrate that reactive astrocytes emerge as a primary consequence of TSC2 loss. These results implicate glial dysfunction as a driver of TSC pathogenesis and highlight reactive astrocytes as potential therapeutic targets for TSC-related neuropathology.\n                  <\/jats:p>","DOI":"10.1038\/s41586-026-11054-w","type":"journal-article","created":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T15:06:07Z","timestamp":1790175967000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["mTORC1 drives cell-autonomous astrocyte reactivity in tuberous sclerosis"],"prefix":"10.1038","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8656-0679","authenticated-orcid":false,"given":"Thomas L.","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7517-6148","authenticated-orcid":false,"given":"John D.","family":"Blair","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7315-0785","authenticated-orcid":false,"given":"Taesun","family":"Yoo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerald A.","family":"Grant","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5598-5092","authenticated-orcid":false,"given":"Dirk","family":"Hockemeyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brenda E.","family":"Porter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0135-0972","authenticated-orcid":false,"given":"Helen S.","family":"Bateup","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,23]]},"reference":[{"key":"11054_CR1","doi-asserted-by":"publisher","first-page":"1345","DOI":"10.1056\/NEJMra055323","volume":"355","author":"PB Crino","year":"2006","unstructured":"Crino, P. 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