mTORC1 drives cell-autonomous astrocyte reactivity in tuberous sclerosis
7 affiliations
- 1Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA
- 2Department of Neuroscience, University of California, Berkeley, Berkeley, CA, USA
- 3Department of Neurosurgery, Lucile Packard Children's Hospital and Stanford University Medical Center, Stanford, CA, USA
- 4Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA
- 5Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA
- 6Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA. [email protected]
- 7Department of Neuroscience, University of California, Berkeley, Berkeley, CA, USA. [email protected]
Abstract
Tuberous Sclerosis Complex (TSC) is a genetic neurodevelopmental disorder associated with early onset epilepsy, intellectual disability and neuropsychiatric disorders. A hallmark of the disorder is cortical tubers, which are focal malformations of brain development containing dysplastic cells with hyperactive mTORC1 signaling. One barrier to developing therapeutic approaches and understanding the origins of tuber cells is the lack of a model system that recapitulates this pathology. To address this, we established a genetically mosaic cortical organoid system that models a somatic “second-hit” mutation, which is thought to drive the formation of tubers in TSC. With this model, we find that loss of TSC2 cell-autonomously promotes the differentiation of astrocytes, which exhibit features of a disease-associated reactive state. TSC2 -/- astrocytes have pronounced changes in morphology and upregulation of proteins that are risk factors for neurodegenerative diseases, such as clusterin and APOE. Using multiplexed immunofluorescence in primary tubers from TSC patients, we show that tuber cells with hyperactive mTORC1 activity also express reactive astrocyte proteins, and we identify a unique population of cells with expression profiles that match those observed in organoids. Together, this work reveals that reactive astrogliosis is a primary feature of TSC that arises early in cortical development. Dysfunctional glia are therefore poised to be drivers of pathophysiology, nominating a potential therapeutic target for treating TSC and related mTORopathies.
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BibTeX
@article{li2026mtorc1,
title = {{mTORC1 drives cell-autonomous astrocyte reactivity in tuberous sclerosis}},
author = {Thomas L. Li and John D. Blair and Taesun Yoo and Gerald Arthur Grant and Dirk F. Hockemeyer and Brenda E. Porter and Helen S. Bateup},
journal = {Nature},
year = {2026},
month = sep,
doi = {10.1038/s41586-026-11054-w},
url = {https://doi.org/10.1038/s41586-026-11054-w},
note = {CC BY},
}
RIS
TY - JOUR
TI - mTORC1 drives cell-autonomous astrocyte reactivity in tuberous sclerosis
AU - Thomas L. Li
AU - John D. Blair
AU - Taesun Yoo
AU - Gerald Arthur Grant
AU - Dirk F. Hockemeyer
AU - Brenda E. Porter
AU - Helen S. Bateup
PY - 2026
DA - 2026/09/23
JO - Nature
DO - 10.1038/s41586-026-11054-w
UR - https://doi.org/10.1038/s41586-026-11054-w
AB - Tuberous Sclerosis Complex (TSC) is a genetic neurodevelopmental disorder associated with early onset epilepsy, intellectual disability and neuropsychiatric disorders. A hallmark of the disorder is cortical tubers, which are focal malformations of brain development containing dysplastic cells with hyperactive mTORC1 signaling. One barrier to developing therapeutic approaches and understanding the origins of tuber cells is the lack of a model system that recapitulates this pathology. To address this, we established a genetically mosaic cortical organoid system that models a somatic “second-hit” mutation, which is thought to drive the formation of tubers in TSC. With this model, we find that loss of TSC2 cell-autonomously promotes the differentiation of astrocytes, which exhibit features of a disease-associated reactive state. TSC2 -/- astrocytes have pronounced changes in morphology and upregulation of proteins that are risk factors for neurodegenerative diseases, such as clusterin and APOE. Using multiplexed immunofluorescence in primary tubers from TSC patients, we show that tuber cells with hyperactive mTORC1 activity also express reactive astrocyte proteins, and we identify a unique population of cells with expression profiles that match those observed in organoids. Together, this work reveals that reactive astrogliosis is a primary feature of TSC that arises early in cortical development. Dysfunctional glia are therefore poised to be drivers of pathophysiology, nominating a potential therapeutic target for treating TSC and related mTORopathies.
SN - 0028-0836
SN - 1476-4687
ER -