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Tuberous sclerosis complex–associated CNS abnormalities depend on hyperactivation of mTORC1 and Akt
Paola Zordan, … , Pietro L. Poliani, Rossella Galli
Paola Zordan, … , Pietro L. Poliani, Rossella Galli
Published February 1, 2018
Citation Information: J Clin Invest. 2018;128(4):1688-1706. https://doi.org/10.1172/JCI96342.
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Research Article Neuroscience

Tuberous sclerosis complex–associated CNS abnormalities depend on hyperactivation of mTORC1 and Akt

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Abstract

Tuberous sclerosis complex (TSC) is a dominantly inherited disease caused by hyperactivation of the mTORC1 pathway and characterized by the development of hamartomas and benign tumors, including in the brain. Among the neurological manifestations associated with TSC, the tumor progression of static subependymal nodules (SENs) into subependymal giant cell astrocytomas (SEGAs) is one of the major causes of morbidity and shortened life expectancy. To date, mouse modeling has failed in reproducing these 2 lesions. Here we report that simultaneous hyperactivation of mTORC1 and Akt pathways by codeletion of Tsc1 and Pten, selectively in postnatal neural stem cells (pNSCs), is required for the formation of bona fide SENs and SEGAs. Notably, both lesions closely recapitulate the pathognomonic morphological and molecular features of the corresponding human abnormalities. The establishment of long-term expanding pNSC lines from mouse SENs and SEGAs made possible the identification of mTORC2 as one of the mediators conferring tumorigenic potential to SEGA pNSCs. Notably, in spite of concurrent Akt hyperactivation in mouse brain lesions, single mTOR inhibition by rapamycin was sufficient to strongly impair mouse SEGA growth. This study provides evidence that, concomitant with mTORC1 hyperactivation, sustained activation of Akt and mTORC2 in pNSCs is a mandatory step for the induction of SENs and SEGAs, and, at the same time, makes available an unprecedented NSC-based in vivo/in vitro model to be exploited for identifying actionable targets in TSC.

Authors

Paola Zordan, Manuela Cominelli, Federica Cascino, Elisa Tratta, Pietro L. Poliani, Rossella Galli

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