ArticleActa neuropathologica communications2015
Tuberous sclerosis complex neuropathology requires glutamate-cysteine ligase.
Article in Acta neuropathologica communications, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 15 citations in OpenAlex.
- Article
- Chronic activation of anti-oxidant pathways and iron accumulation in epileptogenic malformations.Neuropathology and applied neurobiology · 2020Article
- Tuberous Sclerosis Complex as Disease Model for Investigating mTOR-Related Gliopathy During Epileptogenesis.Frontiers in neurology · 2020Review
- Oxidative stress and inflammation in a spectrum of epileptogenic cortical malformations: molecular insights into their interdependence.Brain pathology (Zurich, Switzerland) · 2019Article
- GSK3β Controls mTOR and Prosurvival Signaling in Neurons.Molecular neurobiology · 2018Article
- mTOR Signaling and Neural Stem Cells: The Tuberous Sclerosis Complex Model.International journal of molecular sciences · 2018Review
- Adaptor Complex 2 Controls Dendrite Morphology via mTOR-Dependent Expression of GluA2.Molecular neurobiology · 2018Article
- p62/SQSTM1 Cooperates with Hyperactive mTORC1 to Regulate Glutathione Production, Maintain Mitochondrial Integrity, and Promote Tumorigenesis.Cancer research · 2017Article
- ZBP1 phosphorylation at serine 181 regulates its dendritic transport and the development of dendritic trees of hippocampal neurons.Scientific reports · 2017Article
- Dysregulation of the (immuno)proteasome pathway in malformations of cortical development.Journal of neuroinflammation · 2016Article
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Authors and funding
19 authors at 7 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
introductionTuberous sclerosis complex (TSC) is a genetic disease resulting from mutation in TSC1 or TSC2 and subsequent hyperactivation of mammalian Target of Rapamycin (mTOR). Common TSC features include brain lesions, such as cortical tubers and subependymal giant cell astrocytomas (SEGAs). However, the current treatment with mTOR inhibitors has critical limitations. We aimed to identify new targets for TSC pharmacotherapy.
resultsThe results of our shRNA screen point to glutamate-cysteine ligase catalytic subunit (GCLC), a key enzyme in glutathione synthesis, as a contributor to TSC-related phenotype. GCLC inhibition increased cellular stress and reduced mTOR hyperactivity in TSC2-depleted neurons and SEGA-derived cells. Moreover, patients' brain tubers showed elevated GCLC and stress markers expression. Finally, GCLC inhibition led to growth arrest and death of SEGA-derived cells.
conclusionsWe describe GCLC as a part of redox adaptation in TSC, needed for overgrowth and survival of mutant cells, and provide a potential novel target for SEGA treatment.
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