02088nas a2200241   4500000000100000000000100001008004100002260001500043653002800058653002700086100001700113700001800130700001500148700002000163700002000183700002100203700002000224245007700244856005500321300000900376520144700385022001401832       2026                            d  c2026-09-2310aDevelopmental disorders10aMolecular neuroscience1 aThomas L. Li1 aJohn D. Blair1 aTaesun Yoo1 aGerald A. Grant1 aDirk Hockemeyer1 aBrenda E. Porter1 aHelen S. Bateup00amTORC1 drives cell-autonomous astrocyte reactivity in tuberous sclerosis  uhttps://www.nature.com/articles/s41586-026-11054-w  a1-123 aTuberous sclerosis complex (TSC) is a genetic neurodevelopmental disorder characterized by focal brain malformations called cortical tubers, which are associated with severe, intractable epilepsy1. Tubers are thought to result from somatic second-hit mutations that disrupt the TSC1 or TSC2 genes in neural progenitor cells, driving hyperactive mTORC1 signalling2. Glial abnormalities are commonly observed in tubers3; 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 APOE and CLU. 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.  a1476-4687