mTORC1 activation drives astrocyte reactivity in cortical tubers and brain organoid models of TSC [Bulk RNA-seq]

A critical barrier to developing therapeutic approaches for TSC is a lack of understanding of the developmental origins and molecular profile of tuber cells. To address this, we established genetically mosaic cortical organoid models that recapitulate a somatic “second-hit” mutation, which is proposed to drive tuber cell formation.

We find that loss of TSC2 cell-autonomously promotes the differentiation of astrocytes, which are hypertrophic and have an expression profile consistent with reactive astrocytes in neurodegenerative disorders. Using multiplexed immunofluorescence in TSC patient tubers, we identify a cell population with hyperactive mTORC1 signaling that mirrors the reactive astrocyte signature in organoids. Our results demonstrate that reactive astrogliosis is an early, primary feature of TSC, nominating astrocytes as potential therapeutic targets for TSC and related mTORopathies.