Tuberous sclerosis complex neuropathology requires glutamate-cysteine ligase

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Date
2015-07-30Author
Malik, Anna R
Liszewska, Ewa
Skalecka, Agnieszka
Urbanska, Malgorzata
Iyer, Anand M
Swiech, Lukasz J
Perycz, Malgorzata
Parobczak, Kamil
Pietruszka, Patrycja
Zarebska, Malgorzata M
Macias, Matylda
Kotulska, Katarzyna
Borkowska, Julita
Grajkowska, Wieslawa
Tyburczy, Magdalena E
Jozwiak, Sergiusz
Kwiatkowski, David J
Aronica, Eleonora
Jaworski, Jacek
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Show full item recordAbstract
Abstract
Introduction
Tuberous 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.
Results
The 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.
Conclusions
We 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.