@article{5b66fe77f80b4c80875d537ac599ed09,
title = "SorCS2 Controls Functional Expression of Amino Acid Transporter EAAT3 and Protects Neurons from Oxidative Stress and Epilepsy-Induced Pathology",
abstract = "VPS10P domain receptors emerge as central regulators of intracellular protein sorting in neurons with relevance for various brain pathologies. Here, we identified a role for the family member SorCS2 in protection of neurons from oxidative stress and epilepsy-induced cell death. We show that SorCS2 acts as sorting receptor that sustains cell surface expression of the neuronal amino acid transporter EAAT3 to facilitate import of cysteine, required for synthesis of the reactive oxygen species scavenger glutathione. Lack of SorCS2 causes depletion of EAAT3 from the plasma membrane and impairs neuronal cysteine uptake. As a consequence, SorCS2-deficient mice exhibit oxidative brain damage that coincides with enhanced neuronal cell death and increased mortality during epilepsy. Our findings highlight a protective role for SorCS2 in neuronal stress response and provide a possible explanation for upregulation of this receptor seen in surviving neurons of the human epileptic brain.",
keywords = "EAAC1, EAAT3, VPS10P domain receptors, epilepsy, glutathione, intracellular protein sorting, oxidative stress",
author = "Malik, {Anna R.} and Kinga Szydlowska and Karolina Nizinska and Antonino Asaro and {van Vliet}, {Erwin A.} and Oliver Popp and Gunnar Dittmar and Raphaela Fritsche-Guenther and Kirwan, {Jennifer A.} and Anders Nykjaer and Katarzyna Lukasiuk and Eleonora Aronica and Willnow, {Thomas E.}",
note = "Funding Information: We are indebted to Jasper J. Anink, Andra Eisenmann, Tatjana Pasternack, Kristin Kampf, and Maria Kahlow for expert technical assistance. This work was supported by grants from the European Research Council (BeyOND 335692 to T.E.W.); the Helmholtz Association (AMPro to T.E.W.); the Berlin Institute of Health (Collaborative Research Group 11220008 , to T.E.W.); the European Union {\textquoteright}s Seventh Framework Programme ( FP7/2007-2013 , grant agreement 602102 , EPITARGET, to E.A. and K.L.); the European Union {\textquoteright}s Horizon 2020 Research and Innovation Programme (Marie Sklodowska-Curie grant agreement 722053 , EU-GliaPhD, to E.A.); and Polish Ministry of Science and Education grant W19/7.PR/2014 (to K.L.). Funding Information: We are indebted to Jasper J. Anink, Andra Eisenmann, Tatjana Pasternack, Kristin Kampf, and Maria Kahlow for expert technical assistance. This work was supported by grants from the European Research Council (BeyOND 335692 to T.E.W.); the Helmholtz Association (AMPro to T.E.W.); the Berlin Institute of Health (Collaborative Research Group 11220008, to T.E.W.); the European Union's Seventh Framework Programme (FP7/2007-2013, grant agreement 602102, EPITARGET, to E.A. and K.L.); the European Union's Horizon 2020 Research and Innovation Programme (Marie Sklodowska-Curie grant agreement 722053, EU-GliaPhD, to E.A.); and Polish Ministry of Science and Education grant W19/7.PR/2014 (to K.L.). Publisher Copyright: {\textcopyright} 2019 The Author(s)",
year = "2019",
month = mar,
day = "5",
doi = "10.1016/j.celrep.2019.02.027",
language = "English",
volume = "26",
pages = "2792--2804.e6",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "10",
}