mTORC1 drives cell-autonomous astrocyte reactivity in tuberous sclerosis

Li TL, Blair JD, Yoo T, Grant GA, Hockemeyer D, Porter BE, Bateup HS · 2026 · Nature · Atlas ID LI2026C

What this study shows

Using human brain organoids carrying TSC2 loss-of-function mutations plus patient-derived cortical tuber tissue, shows that hyperactive mTORC1 signaling drives neural progenitors to differentiate into enlarged, pro-inflammatory reactive astrocytes in a cell-autonomous manner (downregulated glutamate transporters, elevated inflammatory cytokines and AD-risk genes APOE/CLU) — independent of seizure activity. Positions glial dysfunction as a primary driver of TSC pathology, not merely a downstream consequence.

Abstract

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Tuberous sclerosis complex (TSC) is a genetic neurodevelopmental disorder characterized by focal brain malformations called cortical tubers, which are associated with severe, intractable epilepsy. Tubers are thought to result from somatic second-hit mutations that disrupt the TSC1 or TSC2 genes in neural progenitor cells, driving hyperactive mTORC1 signalling. Glial abnormalities are commonly observed in tubers; however, whether glia actively cause disease or merely result from chronic seizure activity has remained unclear.

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At a glance

Evidence type	M Molecular — cells, biochemistry, structure Marked M because it is molecular or in-vitro work (model: Human iPSC-derived brain organoids (TSC2-mutant); resected cortical tuber tissue from TSC patients) rather than a whole-organism health-outcome study. That is often exactly where causal biology gets established -- the code says which system the finding was shown in, and nothing about how good the work is.
Study type	5 - Mechanistic / In Vitro
Model system	Human iPSC-derived brain organoids (TSC2-mutant); resected cortical tuber tissue from TSC patients
Journal	Nature
Year	2026
Peer reviewed	Yes
Record last updated	2026-09-23
Source	DOI 10.1038/s41586-026-11054-w · PMID 42778607

Cite this paper

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Li, T. L., Blair, J. D., Yoo, T., Grant, G. A., Hockemeyer, D., Porter, B. E., & Bateup, H. S. (2026). mTORC1 drives cell-autonomous astrocyte reactivity in tuberous sclerosis. Nature. https://doi.org/10.1038/s41586-026-11054-w

@article{LI2026C,
  author       = {Li, T. L. and Blair, J. D. and Yoo, T. and Grant, G. A. and Hockemeyer, D. and Porter, B. E. and Bateup, H. S.},
  title        = {{mTORC1 drives cell-autonomous astrocyte reactivity in tuberous sclerosis}},
  journal      = {Nature},
  year         = {2026},
  doi          = {10.1038/s41586-026-11054-w},
  note         = {PMID: 42778607},
}

Cite this Atlas record

The record is the Atlas's own work — the evidence label, the extracted findings and the links. It is cited as part of the dataset, not as the paper.

Barton, O. (2026). Oliver's mTOR Atlas (record LI2026C) [Data set]. https://mtor-atlas.org/study/LI2026C/ · Dataset DOI 10.5281/zenodo.22059963

@misc{atlas_LI2026C,
  author       = {Barton, Oliver},
  title        = {{Oliver's mTOR Atlas}, record LI2026C},
  howpublished = {Data set},
  year         = {2026},
  url          = {https://mtor-atlas.org/study/LI2026C/},
  doi          = {10.5281/zenodo.22059963}
}