Tuberous Sclerosis Complex Neuropathology Requires Glutamate-cysteine Ligase

Overview

Journal Acta Neuropathol Commun

Publisher Biomed Central

Specialty Neurology

Date 2015 Jul 30

PMID 26220190

Citations 9

Authors

Anna R Malik

Ewa Liszewska

Agnieszka Skalecka

Malgorzata Urbanska

Anand M Iyer

Lukasz J Swiech

Malgorzata Perycz

Kamil Parobczak

Patrycja Pietruszka

Malgorzata M Zarebska

Matylda Macias

Katarzyna Kotulska

Julita Borkowska

Wieslawa Grajkowska

Magdalena E Tyburczy

Sergiusz Jozwiak

David J Kwiatkowski

Eleonora Aronica

Jacek Jaworski

Affiliations

Soon will be listed here.

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.

Citing Articles

Tuberous Sclerosis Complex as Disease Model for Investigating mTOR-Related Gliopathy During Epileptogenesis.

Zimmer T, Broekaart D, Gruber V, van Vliet E, Muhlebner A, Aronica E Front Neurol. 2020; 11:1028.

PMID: 33041976 PMC: 7527496. DOI: 10.3389/fneur.2020.01028.

Chronic activation of anti-oxidant pathways and iron accumulation in epileptogenic malformations.

Zimmer T, Ciriminna G, Arena A, Anink J, Korotkov A, Jansen F Neuropathol Appl Neurobiol. 2019; 46(6):546-563.

PMID: 31869431 PMC: 7308211. DOI: 10.1111/nan.12596.

Oxidative stress and inflammation in a spectrum of epileptogenic cortical malformations: molecular insights into their interdependence.

Arena A, Zimmer T, van Scheppingen J, Korotkov A, Anink J, Muhlebner A Brain Pathol. 2018; 29(3):351-365.

PMID: 30303592 PMC: 8028690. DOI: 10.1111/bpa.12661.

mTOR Signaling and Neural Stem Cells: The Tuberous Sclerosis Complex Model.

Polchi A, Magini A, Meo D, Tancini B, Emiliani C Int J Mol Sci. 2018; 19(5).

PMID: 29772672 PMC: 5983755. DOI: 10.3390/ijms19051474.

GSK3β Controls mTOR and Prosurvival Signaling in Neurons.

Urbanska M, Gozdz A, Macias M, Cymerman I, Liszewska E, Kondratiuk I Mol Neurobiol. 2017; 55(7):6050-6062.

PMID: 29143288 PMC: 5994211. DOI: 10.1007/s12035-017-0823-9.

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