The Characterization of a Subependymal Giant Astrocytoma-Like Cell Line from Murine Astrocyte with mTORC1 Hyperactivation

Abstract

Tuberous sclerosis complex (TSC) is a genetic disorder caused by inactivating mutations in TSC1 (hamartin) or TSC2 (tuberin), crucial negative regulators of the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway. TSC affects multiple organs including the brain. The neurologic manifestation is characterized by cortical tubers, subependymal nodules (SEN), and subependymal giant cell astrocytoma (SEGA) in brain. SEGAs may result in hydrocephalus in TSC patients and mTORC1 inhibitors are the current recommended therapy for SEGA. Nevertheless, a major limitation in the research for SEGA is the lack of cell lines or animal models for mechanistic investigations and development of novel therapy. In this study, we generated TSC1-deficient neural cells from spontaneously immortalized mouse astrocytes in an attempt to mimic human SEGA. The TSC1-deficient cells exhibit mTORC1 hyperactivation and characteristics of transition from astrocytes to neural stem/progenitor cell phenotypes. Rapamycin efficiently decreased mTORC1 activity of these TSC1-deficient cells in vitro. In vivo, TSC1-deficient cells could form SEGA-like tumors and Rapamycin treatment decreased tumor growth. Collectively, our study generates a novel SEGA-like cell line that is invaluable for studying mTORC1-driven molecular and pathological alterations in neurologic tissue. These SEGA-like cells also provide opportunities for the development of novel therapeutic strategy for TSC patients with SEGA.

mTOR Signaling: Recent Progress

“…The mTOR signaling axis controls the survival and development of brain cells and processes of learning and memory, as well as neuronal and synaptic plasticity [ 19 ]. mTOR is mechanistically tightly interconnected with the TSC1/TSC2 complex; therefore, it has been found upregulated in patients with TSC—an autosomal dominant disorder caused by loss-of-function mutations of either TSC1 or TSC2 genes—who develop neurological manifestations, including epilepsy, neuropsychiatric disorders, autism, and brain tumors [ 20 , 21 ]. mTOR inhibition in TSC patients is promising against epilepsy, whereas mTORC1-associated autophagy has been correlated with neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease [ 22 , 23 , 24 ].…”