Acta neuropathologica communications · 2015
Tuberous sclerosis complex neuropathology requires glutamate-cysteine ligase.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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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
Аннотация
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.
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.
Предметные рубрики MeSH
AdolescentAnimalsBrainButhionine SulfoximineCOS CellsCell ProliferationChildChlorocebus aethiopsEnzyme InhibitorsFemaleGlutamate-Cysteine LigaseGreen Fluorescent ProteinsHumansImmunosuppressive AgentsMaleNeuronsRNA, Small InterferingSirolimusTOR Serine-Threonine KinasesTuberous SclerosisTuberous Sclerosis Complex 1 ProteinTuberous Sclerosis Complex 2 ProteinTumor Suppressor ProteinsYoung Adult