title: Tuberous sclerosis complex neuropathology requires glutamate-cysteine ligase.
abstract: BACKGROUND
  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.
authors.affiliation: Laboratory of Molecular and Cellular Neurobiology, International Institute of Molecular and Cell Biology, Warsaw, 02-109, Poland.
authors.forename: Anna R
authors.initials: AR
authors.lastname: Malik
authors.affiliation: Laboratory of Molecular and Cellular Neurobiology, International Institute of Molecular and Cell Biology, Warsaw, 02-109, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Liszewska
authors.affiliation: Laboratory of Molecular and Cellular Neurobiology, International Institute of Molecular and Cell Biology, Warsaw, 02-109, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Skalecka
authors.affiliation: Laboratory of Molecular and Cellular Neurobiology, International Institute of Molecular and Cell Biology, Warsaw, 02-109, Poland.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Urbanska
authors.affiliation: Department of (Neuro)Pathology, Academic Medical Center, Amsterdam, 1105 AZ, The Netherlands.
authors.forename: Anand M
authors.initials: AM
authors.lastname: Iyer
authors.affiliation: Laboratory of Molecular and Cellular Neurobiology, International Institute of Molecular and Cell Biology, Warsaw, 02-109, Poland.
authors.forename: Lukasz J
authors.initials: LJ
authors.lastname: Swiech
authors.affiliation: Laboratory of Molecular and Cellular Neurobiology, International Institute of Molecular and Cell Biology, Warsaw, 02-109, Poland.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Perycz
authors.affiliation: Laboratory of Molecular and Cellular Neurobiology, International Institute of Molecular and Cell Biology, Warsaw, 02-109, Poland.
authors.forename: Kamil
authors.initials: K
authors.lastname: Parobczak
authors.affiliation: Laboratory of Molecular and Cellular Neurobiology, International Institute of Molecular and Cell Biology, Warsaw, 02-109, Poland.
authors.forename: Patrycja
authors.initials: P
authors.lastname: Pietruszka
authors.affiliation: Laboratory of Molecular and Cellular Neurobiology, International Institute of Molecular and Cell Biology, Warsaw, 02-109, Poland.
authors.forename: Malgorzata M
authors.initials: MM
authors.lastname: Zarebska
authors.affiliation: Laboratory of Molecular and Cellular Neurobiology, International Institute of Molecular and Cell Biology, Warsaw, 02-109, Poland.
authors.forename: Matylda
authors.initials: M
authors.lastname: Macias
authors.affiliation: Department of Neurology and Epileptology, Children's Memorial Health Institute, Warsaw, 04-730, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kotulska
authors.affiliation: Department of Neurology and Epileptology, Children's Memorial Health Institute, Warsaw, 04-730, Poland.
authors.forename: Julita
authors.initials: J
authors.lastname: Borkowska
authors.affiliation: Department of Neurology and Epileptology, Children's Memorial Health Institute, Warsaw, 04-730, Poland.
authors.forename: Wieslawa
authors.initials: W
authors.lastname: Grajkowska
authors.affiliation: Division of Pulmonary Medicine and of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02-115, USA.
authors.forename: Magdalena E
authors.initials: ME
authors.lastname: Tyburczy
authors.affiliation: Department of Child Neurology, Medical University of Warsaw, 02-091, Warsaw, Poland.
authors.forename: Sergiusz
authors.initials: S
authors.lastname: Jozwiak
authors.affiliation: Division of Pulmonary Medicine and of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02-115, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Kwiatkowski
authors.affiliation: Department of (Neuro)Pathology, Academic Medical Center, Amsterdam, 1105 AZ, The Netherlands.|Swammerdam Institute for Life Sciences and Center for Neuroscience, University of Amsterdam, Amsterdam, 1090 GE, The Netherlands.|Stichting Epilepsie Instellingen Nederland (SEIN), Heemstede, 2103 SW, The Netherlands.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Aronica
authors.affiliation: Laboratory of Molecular and Cellular Neurobiology, International Institute of Molecular and Cell Biology, Warsaw, 02-109, Poland. jaworski@iimcb.gov.pl.
authors.forename: Jacek
authors.initials: J
authors.lastname: Jaworski
mesh_terms: D000293:Adolescent; D000818:Animals; D001921:Brain / Q000473:pathology*; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D019556:COS Cells; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002648:Child; D002522:Chlorocebus aethiops; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005721:Glutamate-Cysteine Ligase / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008297:Male; D009474:Neurons / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014402:Tuberous Sclerosis / Q000473:pathology*; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D034741:RNA, Small Interfering; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D049452:Green Fluorescent Proteins; D019328:Buthionine Sulfoximine; D058570:TOR Serine-Threonine Kinases; C546365:GCLM protein, human; D005721:Glutamate-Cysteine Ligase; D020123:Sirolimus