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Published on: August 23, 2016
TFEB activation restores migration ability to Tsc1-deficient adult neural stem/progenitor cells
Alessandro Magini1, Alice Polchi1, Danila Di Meo1
1Department of Chemistry, Biology and Biotechnology, University of Perugia, Via del Giochetto, 06122 Perugia, Italy.
Abstract:
Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder caused by mutations in either of two genes, TSC1 or TSC2, resulting in the constitutive activation of the mammalian target of rapamycin complex 1 (mTORC1). mTOR inhibitors are now considered the treatment of choice for TSC disease. A major pathological feature of TSC is the development of subependymal giant cell astrocytomas (SEGAs) in the brain. Nowadays, it is thought that SEGAs could be a consequence of aberrant aggregation and migration of neural stem/progenitor cells (NSPCs). Therefore, reactivation of cell migration of NSPCs might be the crucial step for the treatment of patients. In order to identify potential in vitro targets activating migration, we generated Tsc1-deficient NSPCs. These cells summarize most of the biochemical and morphological characteristics of TSC neural cells, such as the mTORC1 activation, the formation of abnormally enlarged astrocytes-like cells, the reduction of autophagy flux and the impairment of cell migration. Moreover, nuclear translocation, namely activation of the transcription factor EB (TFEB) was markedly impaired. Herein, we show that compounds such as everolimus, ionomycin and curcumin, which directly or indirectly stimulate TFEB nuclear translocation, restore Tsc1-deficient NSPC migration. Our data suggest that reduction of TFEB activation, caused by mTORC1 hyperactivation, contributes to the migration deficit characterizing Tsc1-deficient NSPCs. The present work highlights TFEB as a druggable protein target for SEGAs therapy, which can be additionally or alternatively exploited for the mTORC1-directed inhibitory approach.
Insights
Tuberous sclerosis complex (TSC) involves impaired neural stem/progenitor cell (NSPC) migration due to mTORC1 activation. Targeting transcription factor EB (TFEB) with drugs like everolimus can restore NSPC migration, offering a new therapeutic strategy for TSC-associated brain tumors.
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by TSC1 or TSC2 gene mutations, leading to mTORC1 hyperactivation.
- Subependymal giant cell astrocytomas (SEGAs) are a key neurological manifestation of TSC, potentially arising from abnormal neural stem/progenitor cell (NSPC) aggregation and migration.
- Restoring NSPC migration is a potential therapeutic avenue for TSC-related brain tumors.
Purpose of the Study:
- To investigate the role of transcription factor EB (TFEB) in NSPC migration in the context of TSC.
- To identify potential therapeutic targets for restoring NSPC migration in TSC.
Main Methods:
- Generation of Tsc1-deficient NSPCs to model TSC neural characteristics.
- Assessment of cellular and molecular features including mTORC1 activation, autophagy flux, and cell migration.
- Evaluation of compounds (everolimus, ionomycin, curcumin) that stimulate TFEB nuclear translocation.
Main Results:
- Tsc1-deficient NSPCs exhibited impaired migration, reduced autophagy, and defective TFEB nuclear translocation, mirroring TSC neural cell phenotypes.
- Compounds stimulating TFEB nuclear translocation, such as everolimus, successfully restored migration in Tsc1-deficient NSPCs.
- mTORC1 hyperactivation in TSC contributes to impaired TFEB activation and subsequent NSPC migration deficits.
Conclusions:
- Reduced TFEB activation, driven by mTORC1 hyperactivation, is a key factor in the migration impairment of TSC-related NSPCs.
- TFEB represents a druggable target for therapeutic strategies aimed at treating SEGAs in TSC patients.
- Targeting TFEB offers a complementary or alternative approach to existing mTORC1-inhibitor therapies for TSC.
