A UC Berkeley team reported Wednesday, Sept. 23, in Nature (opens in new tab) that human brain organoids modeling tuberous sclerosis complex (TSC) produce hyperreactive astrocytes as a primary consequence of losing both copies of the TSC2 gene, according to university and EurekAlert summaries of the peer-reviewed paper.
TSC is a leading genetic cause of early-onset, often drug-resistant epilepsy, with potato-shaped cortical “tubers” that can require surgery. Helen Bateup’s lab and collaborators used mosaic organoids to mimic a second-hit mutation, then tracked cell fates with single-cell transcriptomics and cyclic immunostaining. Mutant progenitors preferentially formed enlarged, pro-inflammatory astrocytes that downregulated glutamate-transporter expression and raised inflammatory cytokine signals—even without seizures in the dish.
The same reactive-astrocyte protein signature appeared in high mTORC1-activity cells within resected tubers from patients treated surgically for seizures, the Nature (opens in new tab) abstract and Berkeley News (opens in new tab) account said. Researchers argued glia may help drive lesions rather than only appear after chronic seizures.
Existing immunosuppressants that calm reactive glia are discussed as possible adjuncts to mTOR pathway drugs such as rapalogs, which can carry metabolic and immune side effects. The Event Log notes that organoid and tissue findings do not by themselves prove a new approved therapy; clinical testing would still be required. Co-first authors Thomas Li and John Blair led the work with Stanford neurosurgery and neurology collaborators; funding included NINDS and Chan Zuckerberg Biohub support.